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All 18 posts Subject: Glennon Digest Please login to post Down

Aurelius
(Active Asperger Archivist)
05-13-04 22:43
No 506981
      Glennon Digest

Please put the links into catagories by compounds or methods.

Also, use color or different text styles to distinguish the titles.

Other than that, You've got quite the collection- nice work.

Act quickly or not at all.

Ganesha
(Hive Bee)
05-13-04 22:56
No 506983
      All his pubs to date:

http://www.pharmacy.vcu.edu/glennon/RAG_1.htm

'I' am a crowd, obeying as many laws As it has members. Chemically impure Are all 'my' beings.

Aurelius
(Active Asperger Archivist)
05-14-04 02:58
No 507037
      Contribution

Now that's a contribution!

Good job.

Act quickly or not at all.

Lego
(Hive Bee)
05-14-04 23:03
No 507209
User Picture       Lots of work to bee done....

Aurelius: Don't worry, everthing will bee formatted in a proper way. This is just the beginning....
What would bee your suggestion for the categories?

5-HT_2A/C ligands
other 5-HT ligands
Stimulants and psychoactive drugs
Pharmacology of psychoactive drugs
Everything else

All articles of interest for the Hive (5-HT_2A/C agonists, stimulants, etc.) will bee added step by step.
All bees who which to support this digest: Please copy and scan the relevant articles (not J. Med. Chem. as they are availabe online). Thanks!

The tendency is to push it as far as you can

7is
(Hive Bee)
05-14-04 23:50
No 507217
User Picture       Elsevier

All bees who which to support this digest: Please copy and scan the relevant articles (not J. Med. Chem. as they are availabe online). Thanks!

As I have access to most of the journals published by Elsevier, http://www.sciencedirect.com/ (they have online articles back to year 1939), I can upload them to this thread later. But now I have to get some sleep. blush

xaja
(Newbee)
05-15-04 21:33
No 507366
      Hey this is interesting

This is interesting, this guy's research on serotonin receptors makes great reading. The more I read on the Hive the more I want to branch into pharmacology. So to you bees who keep posting these links, thanx, and keep it up. cool

"I used to crash parties and Maserati's"

hypo
(Hive Addict)
05-15-04 21:36
No 507368
      what?

> This is interesting, this guy's research on serotonin receptors makes great reading.

i can't think of _anything_ more dull than receptor binding
studies! tongue

http://www.animalyawns.com

_mu_
(Hive Bee)
05-15-04 22:41
No 507375
      ..unless you have a dozen of white fluffy...

..unless you have a dozen of white fluffy powders, all 5ht2a-agonists, in front of you :-)

hypo
(Hive Addict)
05-15-04 22:44
No 507376
      alright...

...in scientisticus testing is a different thing altogether... laugh

http://www.animalyawns.com

Rhodium
(Chief Bee)
05-16-04 19:23
No 507543
User Picture       Here's one of the more odd ones
(Rated as: good read)

Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study
Richard A. Glennon, Abd EI-Kader M. Ismaiel, Bruce G. McCarthy, and Stephen J. Peroutka
European Journal of Pharmacology 168, 387-392 (1989) (https://www.rhodium.ws/pdf/glennon.arylpiperazines.5ht3.pdf)

^{The Hive - Clandestine Chemists Without Borders}

7is
(Hive Bee)
05-19-04 23:02
No 508288
User Picture       All the missing Life Sciences articles part 2
(Rated as: excellent)

Discriminative stimulus properties of the serotonergic agent 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)
Richard A. Glennon
Life Sci. 1986 Sep 1;39(9):825-30

Using a two-lever drug discrimination procedure, six rats were trained to discriminate 0.5 mg/kg of racemic 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) from saline. Once trained, the animals demonstrated a dose-related decrease in discriminative performance upon administration of lower doses of DOI (ED50 = 0.16 mg/kg). DOI-stimulus generalization occured with the putative 5-HT2 agonist DOM (ED50 = 0.49 mg/kg), but not with the 5-HT1A agonist 8-OH DPAT, or the 5-HT1B agonist TEMPP. Furthermore, the DOI stimulus could be antagonized by pretreatment of the animals with the 5-HT2 antagonist ketanserin. The present results, coupled with the prior demonstration that DOI possesses a significant affinity and selectivity for 5-HT2 binding sites, suggest that the discriminative stimulus effects of DOI may be 5-HT2-mediated.

Effect of 5-HT2-selective agonists on cat platelet aggregation
Mark R. Seggel, G. D. Qureshi and Richard A. Glennon
Life Sci. 1987 Aug 31;41(9):1077-81

The effects of the 5-HT2-sselective agonists 1-(4-bromo-2, 5-dimethoxyphenyl) -2- aminopropane (DOB) and 1- (2, 5-dimethenyl4-iodophenyl) -2- aminopropane (DOI) on cat platelet aggregation were investigated and compared with those produced by serotonin (5-HT) and a positional isomer of DOB (i.e., isoDOB). Serotonin, DOB, and DOI enhanced the aggregation of platelets induced by a suboptimal concentration of ADP. This effect was completely inhibited by pre-incubation of the platelet suspension with the 5-HT2-selective antagonist ketanserin. IsoDOB, an isomer of DOB with a very low affinity for central 5-HT2 binding sites, was inactive in the platelet aggregation assay. The present results are consistent with the proposed role of 5-HT2 receptors in serotonin-induced platelet aggregation.

Stereochemistry of the metabolism of MDMA to MDA
Robert L. Fitzgerald, Robert V. Blanke, John A. Rosecrans and Richard A. Glennon
Life Sci. 1989;45(4):295-301

The chiral derivatizing reagent N-trifluoroacetyl-L-propyl chloride (LPTC) was used to form diastereomers of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) which were resolved on an achiral gas chromatographic column using a mass spectrometer as a detector. Rats were subcutaneously dosed with 40 mg/kg of (+/−) MDMA·HCl and blood was obtained by decapitation four hours after dosing. Plasma was separated and extracted. The extract was derivatized on-column with LTPC. In addition to the two MDMA isomers, the demethylated metabolites, S(+) and R(−)-MDA were identified. In all experimental groups (male rats, food deprived male rats, female rats, post partum female rats, and mice) dosed with racemic MDMA, higher levels of the S(+) isomer of MDA relative to the R(−) MDA isomer were observed. This may be significant since it has been shown that the S(+) isomer of MDMA is the more neurotoxic isomer of the racemic drug of abuse MDMA.

Multiple populations of serotonin receptors may modulate the behavioral effects of serotonergic agents
Richard A. Glennon, Nissar A. Darmani and Billy R. Martin
Life Sci. 1991;48(26):2493-8

In order to establish a functional role for the various populations of serotonin (5-HT) receptors, behavioral studies have been conducted over the past decade with serotonergic agonists and antagonists. And, although there is reason to believe that certain behavioral effects may be mediated via particular populations of 5-HT receptors, evidence now suggests that some serotonin-mediated behaviors may be modulated by the interaction of serotonergic agents at multiple subtypes of 5-HT receptors. The generality of these effects, and the exact mechanism(s) by which they occur, have yet to be elucidated. Nevertheless, over the past year, results from several different laboratories provide a growing recognition of this novel phenomenon.

7is
(Hive Bee)
06-09-04 17:42
No 512438
User Picture       All the missing PBB articles part 1
(Rated as: excellent)

Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT2 receptor function.
Darmani NA, Martin BR, Glennon RA.
Pharmacol Biochem Behav. 1992 Mar;41(3):519-27.

Inhibition of 5-HT2 receptor-mediated head-twitch response by cocaine via indirect stimulation of adrenergic alpha 2 and serotonergic 5-HT1A receptors.
Darmani NA, Martin BR, Pandey U, Glennon RA.
Pharmacol Biochem Behav. 1991 Feb;38(2):353-7.

Cocaine inhibits the 5-HT2-mediated (±)-DOI-induced head-twitch response (HTR) in mice in a dose-dependent manner. In order to investigate the possible inhibitory mechanism(s) of cocaine on 5-HT2 receptor function, we studied the effects of the selective adrenergic alpha2 receptor antagonist yohimbine and the beta-adrenergic/5-HT1 receptor antagonist alprenolol, and the 5-HT3 antagonist ICS 205–930 on the inhibitory action of cocaine on the (±)-DOI-induced HTR. Neither yohimbine (0.1 and 0.5 mg/kg) nor alprenolol (10 mg/kg) pretreatment had any significant effect on the (±)-DOI-induced HTR. However, both antagonists prevented the inhibitory effects of cocaine on the (±)-DOI-induced HTR. The 5-HT3 antagonist ICS 205–930 neither produced HTR nor decreased the (±)-DOI-induced HTR frequency. The present results suggest that cocaine inhibits 5-HT2 receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and thus indirectly stimulating the respective inhibitory adrenergic alpha2 and serotonergic 5-HT1A receptors. Furthermore, cocaine's 5-HT3 antagonist properties appear not to play a role in the inhibition of head-twitch behavior.

Do functional relationships exist between 5-HT1A and 5-HT2 receptors?
Darmani NA, Martin BR, Pandey U, Glennon RA.
Pharmacol Biochem Behav. 1990 Aug;36(4):901-6.

To investigate the possible functional relationship between 5-HT1 and 5-HT2 receptors, we studied the effects of a nonselective 5-HT agonist (5-MeO DMT), a 5-HT1A-selective (8-OH-DPAT) and a 5-HT1B/5-HT1C-selective (TFMPP) agonist on the head-twitch behavior induced by the putative 5-HT2-selective receptor agonist (±)-DOI. In the mouse (±)-DOI produced the head-twitch response in a dose-dependent manner and (−)-DOI was twice as potent as the (+) isomer. Selective 5-HT2 antagonists, ketanserin and spiperone, dose-dependently inhibited the (±)-DOI-induced head-twitch response. The nonselective and the 5-HT1A-selective agonists also dose-dependently reduced the behavior, whereas 5-HT1B/5-HT1C-selective agonist (TFMPP) failed to affect the (±)-DOI-induced response. Taken together with previously published literature data, we propose a 5-HT1A inhibitory action on the 5-HT2 receptor-mediated response when induced by its selective agonist (±)-DOI.

Further studies on the dose-dependent stimulus properties of 5-methoxy-N,N-dimethyltryptamine.
Young R, Rosecrans JA, Glennon RA.
Pharmacol Biochem Behav. 1986 Dec;25(6):1207-10.

Twenty-two rats were trained to discriminate either 1.5 mg/kg or 3.0 mg/kg of 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT) from saline in a standard two-lever operant procedure. Once responding was stable, various doses of several serotonin (5-HT) antagonists, i.e., cyproheptadine (CYP), methysergide (UML), cinanserin (CIN), and methergoline (MCE), were administered in combination with 5-OMe DMT, to assess the ability of each antagonist to attenuate each 5-OMe DMT-stimulus. The 5-OMe DMT-stimulus at 1.5 mg/kg was completely antagonized by CYP, and was partially attenuated by CIN and MCE. UML had negligible effects on 5-OMe DMT-appropriate responding. In the 3.0 mg/kg 5-OMe DMT-trained rats, UML and MCE partially blocked the 5-OMe DMT-stimulus; CYP and CIN had no significant effect on 5-OMe DMT-appropriate responding. The results suggest that until the in vivo effects and mechanism of action of 5-OMe DMT and certain 5-HT antagonists are better understood, caution is advised when conclusions are drawn from studies employing these agents.

Discriminative stimulus properties of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT).
Glennon RA.
Pharmacol Biochem Behav. 1986 Jul;25(1):135-9.

Using a two-lever operant procedure, eleven rats were trained to discriminate 0.2 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT) from saline using a variable-interval 15 sec schedule of reinforcement. Once trained, these animals were used in a series of stimulus generalization and stimulus antagonism studies. The 8-OH DPAT-stimulus did not generalize to the 5-HT1B agonist 1- (3-trifluoromethylphenyl)piperazine (TFMPP) or the 5-HT2 agonist 1(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), nor could it be attenuated by pre-treatment of the animals with the 5-HT2 antagonist ketanserin. Low doses of spiperone and propranolol were without effect on 8-OH DPAT-appropriate responding, whereas higher doses of these agents resulted in disruption of behavior. Some preliminary structure-activity data were also obtained using several related tetralin analogs. The results of this study demonstrate that the serotonin agonist 8-OH DPAT serves as a discriminative stimulus in rats and that it produces stimulus effect that are probably not 5-HT1B or 5-HT2-mediated.

Mechanistic studies on DOM as a discriminative stimulus.
Glennon RA, Hauck AE.
Pharmacol Biochem Behav. 1985 Dec;23(6):937-41.

Ten rats were trained to discriminate racemic DOM (1.0 mg/kg, IP) from saline using a standard two-lever operant procedure. Once responding was stable, these animals were administered doses of lisuride and the purported 5-HT1 agonist 8-OH DPA in tests of stimulus generalization. DOM-stimulus generalization occurred with lisuride, but not with 8-OH DPAT. These animals were also administered doses of LY-53,857, ritanserin, CP-52,215, and THT in tests of stimulus antagonism. Each of these agentspossesses a significant affinity for 5-HT2 binding sites, and each effectively attenuated the DOM-stimulus. These results, coupled with our earlier findings, support the hypothesis that DOM may be producing its stimulus effects via a 5-HT2-related mechanism.

Structure-activity studies on methoxy-substituted phenylisopropylamines using drug discrimination methodology.
Glennon RA, Young R, Hauck AE.
Pharmacol Biochem Behav. 1985 May;22(5):723-9.

Eighteen rats were trained to discriminate 1.0 mg/kg of (+)-amphetamine sulfate from saline in a two-lever operant procedure. Once responding was stable, these animals were administered various doses of sixteen different methoxy-substituted phenyliso-propylamines in tests of stimulus generalization. Of three possible mono-methoxyphenylisopropylamines, all three produced amphetamine-appropriate responding, but none was as potent as racemic amphetamine. The amphetamine-stimulus did not completely generalize to any of the di- or tri-methoxyphenylisopropylamines.

Comparison of behavioral properties of di- and tri-methoxyphenylisopropylamines.
Glennon RA, Young R.
Pharmacol Biochem Behav. 1982 Oct;17(4):603-7.

Prominent among the class of hallucinogenic phenylisopropylamines is the 2,5-dimethoxy substitution pattern; this pattern has long been recognized as being an important feature of the more potent agents within this class. The purpose of this present study was to explore the behavioral properties of a series of methoxylated phenylisopropylamines in order to determine the effect of other substitution patterns and the relative importance of individual methoxy groups. Rats, trained to discriminate the hallucinogenic agent 2,5-dimethoxy-4-methyl-phenylisopropylamine (DOM) from saline in a two-lever drug discrimination task, were challenged with a series of di- and trimethoxyphenylisopropylamines (i.e., DMA and TMA derivatives). DOM-stimulus generalization was found to occur with 2,4-DMA but not with 2,3-DMA, 2.6-DMA, or 3,5-DMA; generalization also occurred with 2,3,4-TMA, 2,3,5-TMA, 2,4,6-TMA and 3,4,5-TMA. The 2,4-dimethoxy pattern also emerges as an important feature among the more active agents.

Pharmacological characterization of ear-scratch response in mice as a behavioral model for selective 5-HT2-receptor agonists and evidence for 5-HT1B- and 5-HT2-receptor interactions.
Darmani NA, Martin BR, Pandey U, Glennon RA.
Pharmacol Biochem Behav. 1990 Sep;37(1):95-9.

(±)1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI], a phenylisopropylamine hallucinogen, is a 5-HT2-receptor agonist. The drug induced a dose-dependent increase in ear-scratch response (ESR) in mice, and the R(−)-isomer was more than 6 times as potent as its S(+)-enantiomer. The induced behavior was potently inhibited by selective 5-HT2-receptor antagonists such as ketanserin and spiperone. The (±)-DOI-induced ESR is also inhibited by stimulation of 5-HT1-receptors and the inhibition seems to be through a 5-HT1B-receptor mechanism. Thus, taken together, the present investigation indicates that ESR is due to selective stimulation of 5-HT2-receptors and that simultaneous costimulation of 5-HT1B-receptors inhibits the induced behavior. The study further suggests that the inability of the indolealkylamine hallucinogens to induce ESR is due to simultaneous excitation of 5-HT1B-receptors which are inhibitory to induction of ESR. Moreover, the data suggest possible inhibitory control mechanisms through 5-HT1-receptor subtypes to provide a damping mechanism to reduce excessive 5-HT2-receptor excitation due to exogenous drug stimulation or pathological conditions.

A comparison of the behavioral effects of DOM homologs.
Glennon RA, Young R, Rosecrans JA.
Pharmacol Biochem Behav. 1982 Apr;16(4):557-9.

Twenty-four rats, trained to discriminate 1.0 mg/kg of (±)-DOM, i.e., (±)-2,5-dimethoxy-4-methylphenylisopropylamine, from saline under a VI-15 schedule of reinforcement, were challenged with a series of DOM homologs. The agents examined included the 4-ethyl (DOET), -propyl (DOPR), -butyl (DOBU), -tertiary butyl (DOTB) and -amyl (DOAM) derivatives as well as the R(−)- and S(+)-isomers of DOET. The (±)-DOM stimulus was found to generalize to all of the agents, except DOTB and DOAM, where only partial generalization occurred. The results suggest that the stimulus properties produced by the latter two compounds may differ from those of the remainder of the series. Furthermore, the ED50 values obtained, for those compounds to which the DOM-stimulus generalized, correlated significantly (r2=0.94) with the human hallucinogenic potencies of these agents.

Discriminative stimulus properties of DOM and several molecular modifications.
Glennon RA, Young R, Rosecrans JA.
Pharmacol Biochem Behav. 1982 Apr;16(4):553-6.

Rats trained to discriminate racemic 2,5-dimethoxy-4-methylphenylisopropylamine, (±)-DOM (1.0 mg/kg), from saline in a two-lever drug discrimination task were challenged with the optical isomers of DOM as well as with several related agents which represent minor molecular modifications of the DOM structure. Generalization of the (±)-DOM stimulus was found to occur to R(−)-DOM, S(+)-DOM, (±)-2,5-dimethoxyphenylisopropylamine (2,5-DMA), R(−)-2,-5-DMA, and the 2-demethyl derivative of (±)-DOM. The 3-methyl positional isomer of (±)-DOM was found to produce only 34% DOM-appropriate responding at the highest dose tested while administration of S(+)-2,5-DMA and the 5-demethyl derivative of (±)-DOM resulted in disruption of behavior.

7is
(Hive Bee)
06-09-04 20:21
No 512466
User Picture       All the missing PBB articles part 2
(Rated as: excellent)

DOM and related 2,5-dimethoxy-4-alkylphenylisopropylamines: behavioral and serotonin receptor properties.
Glennon RA, Doot DL, Young R.
Pharmacol Biochem Behav. 1981 Mar;14(3):287-92.

Using an isolated rat fundus preparation, the 4-methyl (DOM), ethyl (DOET), propyl (DOPR) butyl (DOBU), tertiary butyl (DOTB) and amyl (DOAM) derivatives of 2,5-dimethoxy-phenylisopropylamine (2,5-DMA) were found to possess quite similar serotonin receptor affinities (pA2=7.02–7.22). The fundus preparation could not be used to determine pD2 values because all of the compounds were found to interact in an agonistic manner both with serotonin and PRT (phenoxybenzamine resistant tryptamine) receptors. Administration of DOET, DOPR, DOBU, DOTB and DOAM to animals (rats) trained to discriminate 5-OMe DMT from saline resulted only in partial generalization. While each of these agents possesses a high 5-HT receptor affinity, and while their behavioral effects might, therefore, involve a serotonergic component, the stimulus properties of these compounds are qualitatively dissimilar to those produced by the training dose of 5-OMe DMT.

Stimulus properties of ring-methyl amphetamine analogs.
Higgs RA, Glennon RA.
Pharmacol Biochem Behav. 1990 Dec;37(4):835-7.

There are three possible ring-substituted methyl amphetamines (or tolylaminopropanes; TAPs): oTAP, mTAP and pTAP. These agents are positional isomers of methamphetamine. Although all three isomers have been previously reported to possess amphetamine-like character, few studies have examined all three agents in comparison with (+)amphetamine. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline under a variable-interval 15-sec schedule of reinforcement, tests of stimulus generalization were conducted with the three positional isomers. Only oTAP (ED50 DOSE=4.1 mg/kg) completely substituted for (+)amphetamine. mTAP and pTAP resulted only in partial (ca. 50% amphetamine-appropriate responding) generalization. It is concluded that oTAP is capable of producing amphetamine-like stimulus effects and that it is approximately one-tenth as potent as (+)amphetamine; however, because the partial generalization produced by mTAP and pTAP was followed by disruption of behavior at slightly higher doses, it cannot be reliably stated that these latter two isomers lack amphetamine-like character.

5-HT3 agonist 2-methylserotonin as a training drug in discrimination studies.
Glennon RA, Young R, Dukat M.
Pharmacol Biochem Behav. 1992 Feb;41(2):361-4.

Using a standard two-lever operant procedure, rats were trained to discriminate 5 mg/kg of the 5-HT3 agonist 2-methylserotonin (2-Me 5-HT;ED50 = 2.6 mg/kg) from saline using a VI 15-s schedule of reinforcement. The 2-Me 5-HT stimulus dinot generalize to the 5-HT1/5-HT2 agonist 5-methox-N, N-dimethyltryptamine, but did generalize to the new 5-HT3 agonist 1-(m-chlorophenyl)biguanide (ED50 = 1.6 mg kg). The 5-HT3 antagonist ICS 205–930 potently antagonized the 2-Me 5-HT stimulus (ID50 = 0.001 mg/kg), whereas its quaternary amine analog, which does not readily penetrate the blood-brain barrier, failed to completely antagonize the 2-Me 5-HT stimulus at a 10, 000-fold higher dose. The results of the present investigation show that 2-Me 5-HT serves as a discriminative stimulus in rats when paired when saline and suggest that its properties are likely mediated via a central 5-HT3 mechanism. As such, this is the first demonstration that a 5-HT3 agonist can be used as a training drug in drug discrimination studies.

Approaches to molecular modeling studies and specific application to serotonin ligands and receptors.
Westkaemper RB, Glennon RA.
Pharmacol Biochem Behav. 1991 Dec;40(4):1019-31.

Molecular modeling studies are useful in as much as they may allow us to understand the activity and selectivity of currently existing agents, and, furthermore, may aid in the design of completely novel therapeutic agents. There are two basic modelling strategies: the ligand-ligand approach and the ligand-receptor approach. Both approaches possess certain inherent advantages and disadvantages and, in addition, make certain assumptions about the agents and/or receptors being investigated. Keeping with the spirit of this minisymposium, we describe these two approaches, their general usefulness, and their limitations. Using serotonin (5-HT) receptors as a focal point, we review and provide novel examples of molecular modeling studies involving both strategies. Presented for the first time are examples of ligand-receptor models to account for the binding of serotonergic agents at 5-HT2 and 5-HT1C receptors.

Serotonin receptors and their ligands: a lack of selective agents.
Glennon RA, Dukat M.
Pharmacol Biochem Behav. 1991 Dec;40(4):1009-17.

Four major families of serotonin (5-hydroxytryptamine; 5-HT) receptors have been identified: 5-HT1, 5-HT2, 5-HT3 and 5-HT4. At this time, there is a general consensus that the 5-HT1 family can be further subdivided into 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1P subpopulations. In addition, there are several other populations of less well-defined 5-HT receptors. The purpose of this presentation is to discuss 5-HT receptor nomenclature and the agents that are commonly used to investigate each receptor population in as much as it will serve to provide background for the remainder of the symposium. There is presently available an abundance of serotonergic agents; however, these agents are only semiselective, and none can be considered truly selective for a particular population of 5-HT receptors. As useful as these agents have been for the identification and characterization of 5-HT receptors, there remains a need for the development of new, more selective ligands.

Central stimulants as discriminative stimuli. Asymmetric generalization between (-)ephedrine and S(+)methamphetamine.
Bondareva TS, Young R, Glennon RA.
Pharmacol Biochem Behav. 2002 Dec;74(1):157-62.

Central stimulants readily serve as training stimuli in drug discrimination studies and typically substitute for one another in tests of stimulus generalization regardless of which is used as training drug. We have previously found that, although substitution occurs between (+)amphetamine and (−)ephedrine, substitution did not occur upon administration of S(+)methamphetamine to (−)ephedrine-trained animals. In the present investigation, rats were trained to discriminate S(+)methamphetamine (1 mg/kg) from saline vehicle and tests of stimulus generalization were performed with several stimulants, including (−)ephedrine. The S(+)methamphetamine stimulus (ED50=0.06 mg/kg) generalized to R(−)methamphetamine (ED50=1.61 mg/kg), S(+)amphetamine (ED50=0.28 mg/kg), S(−)methcathinone (ED50=0.21 mg/kg), methylphenidate (ED50=0.28 mg/kg), cocaine (ED50=3.68 mg/kg) and (−)ephedrine (ED50=13.1 mg/kg). Hence, stimulus generalization between S(+)methamphetamine and (−)ephedrine is apparently asymmetrical. In a companion study, R(−)methamphetamine was administered to rats trained to discriminate (−)ephedrine (4 mg/kg); substitution occurred and R(−)methamphetamine (ED50=0.92 mg/kg) was found to be nearly equipotent with (−)ephedrine (ED50=0.8 mg/kg). Although the exact basis for the observed results are unclear, they are discussed in terms of the different effects of (−)ephedrine and the methamphetamine optical isomers on neurotransmitter release and reuptake.

Effect of 1-(3,4-methylenedioxyphenyl)-2-aminopropane and its optical isomers in PMMA-trained rats.
Glennon RA, Young R.
Pharmacol Biochem Behav. 2002 May;72(1-2):307-11.

1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA) is a drug of abuse that is known to produce stimulus effects similar to those of the stimulant phenylalkylamine (+)amphetamine and the hallucinogenic phenylalkylamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Earlier, a working model was described to account for the stimulus effects produced by phenylalkylamines. Such agents can produce one or more of three distinct effects: an amphetamine effect, a DOM effect and a third effect that is typified by the agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). Because MDA is known to produce two of the three effects, in the present investigation, we sought to determine if racemic MDA or either of its optical isomers could produce a PMMA-like effect in animals. Administration of S(+)MDA, R(−)MDA and (±)MDA to rats trained to discriminate 1.25 mg/kg of PMMA from saline vehicle under a VI 15-s schedule of reinforcement resulted in substitution in each case. (±)MDA and S(+)MDA were nearly equipotent and several fold more potent than R(−)MDA. The results are not only consistent with the proposed model but also identify (±)MDA as the first phenylalkylamine shown to produce all three types of stimulus effects (i.e., amphetamine-like, DOM-like and PMMA-like) in rats.

Effect of PMA optical isomers and 4-MTA in PMMA-trained rats.
Dukat M, Young R, Glennon RA.
Pharmacol Biochem Behav. 2002 May;72(1-2):299-305.

1-(4-Methoxyphenyl)-2-aminopropane (PMA) and its sulfur analog, 1-(4-methylthiophenyl)-2-aminopropane (4-MTA), have been misrepresented as the controlled substance analog, N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; "Ecstasy"). Because MDMA has been shown to produce both amphetamine-like and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA)-like stimulus effects in rats, we examined S(+)PMA, R(−)PMA and 4-MTA in rats trained to discriminate either PMMA (1.25 mg/kg) or (+)amphetamine (1.0 mg/kg) from saline vehicle. The sulfur analog of PMMA (i.e., 4-MTMA) was also examined. The PMMA stimulus generalized to R(−)PMA (ED50=0.4 mg/kg), whereas S(+)PMA produced a maximum of 72% PMMA-appropriate responding. 4-MTA (ED50=0.3 mg/kg) also substituted for PMMA, but 4-MTMA produced a maximum of only 36% PMMA-appropriate responding. None of the four agents substituted for (+)amphetamine. Hence, like MDMA, R(−)PMA and 4-MTA are capable of producing PMMA stimulus effects in rats, but unlike MDMA, neither agent substituted for (+)amphetamine.

PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA.
Rangisetty JB, Bondarev ML, Chang-Fong J, Young R, Glennon RA.
Pharmacol Biochem Behav. 2001 May-Jun;69(1-2):261-7.

Psychoactive phenylisopropylamines can produce one or more of several different stimulus effects in animals. These effects are typified by the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), the central stimulant amphetamine, and by N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA), an agent whose actions are not yet well understood. The optical isomers of two phenylisopropylamines known to lack DOM and amphetamine-stimulus character, that is N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane (MBDB) and 1-(3,4-dimethoxyphenyl)-2-aminopropane (3,4-DMA), were examined in rats trained to discriminate 1.25 mg/kg of PMMA from vehicle. The PMMA stimulus (ED50=0.4 mg/kg) generalized to all four agents: S(+)-MBDB (ED50=0.8 mg/kg), R(−)-MBDB (ED50=2.0 mg/kg), S(+)-3,4-DMA (ED50=2.6 mg/kg) and R(−)-3,4-DMA (ED50=3.9 mg/kg). The results show that these agents produce stimulus effects similar to those produced by PMMA. Both isomers of MBDB have been previously demonstrated to substitute for N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) in rats trained to discriminate MDMA from vehicle, but MBDB-trained animals failed to recognize DOM or amphetamine. Similar results were obtained with the 3,4-DMA optical isomers in the present investigation using rats trained to discriminate MDMA, DOM or (+)-amphetamine from vehicle; both isomers of 3,4-DMA substituted for an MDMA stimulus, but not for a DOM or amphetamine stimulus. Taken together, the evidence suggests that PMMA, S(+)-MBDB, R(−)-MBDB, S(+)-3,4-DMA, R(−)-3,4-DMA, and S(+)-MDMA can produce common stimulus effects in rats. The present findings also better define the PMMA stimulus and the structural requirements necessary to produce this type of stimulus effect.

Stimulus effects of phenylpropanolamine optical isomers in (+)amphetamine-trained rats.
Young R, Glennon RA.
Pharmacol Biochem Behav. 2000 Jul;66(3):489-94.

MDMA stimulus generalization to the 5-HT1A serotonin agonist 8-hydroxy-2-(di-n-propylamino)tetralin.
Glennon RA, Young R.
Pharmacol Biochem Behav. 2000 Jul;66(3):483-8.

7is
(Hive Bee)
06-09-04 22:17
No 512488
User Picture       some problems and a book chapter

I couldn´t upload anymore articles, because it says that I already have uploaded 11 pdf´s(maximum). I have linked all the pdf´s already in this thread. Can some moderator fix that?

Here is a book chapter by Glennon:
R.A. Glennon and R. Young (1987), The study of structure-activity relationships using drug discrimination methodology. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 373-390). New York: Springer-Verlag.

http://www.addictionscience.net/MARPADc18.htm

7is
(Hive Bee)
06-10-04 10:21
No 512562
User Picture       All the missing PBB articles part 3
(Rated as: excellent)

(+)Amphetamine-stimulus generalization to an herbal ephedrine product.
Glennon RA, Young R.
Pharmacol Biochem Behav. 2000 Apr;65(4):655-8.

We have previously demonstrated that a (+)amphetamine stimulus generalizes both to (−)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal (IP) administration of 1.0 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a standard two-lever drug discrimination procedure, the present investigation shows that the (+)amphetamine stimulus generalizes to (+)amphetamine (ED50 = 1.0 mg/kg) when administered via the intragastric (IG) route, and that (+)amphetamine appears about 2.5-fold less potent when administered via the IG route compared to the IP route. Likewise, (−)ephedrine (ED50 = 10.8 mg/kg) and caffeine (ED50 = 32.9 mg/kg) are also 2.5-fold less potent when administered via the IG route compared to their potency when administered via the IP route. The (+)amphetamine stimulus also generalizes to an IG-administered herbal preparation (i.e., Herbal XTC®; the herbal preparation possesses an approximate potency roughly comparable to what might have been expected on the basis of its reported ephedrine and/or caffeine content. These results demonstrate, for the first time, that an ephedrine-containing herbal preparation can produce a (+)amphetamine-like effect in animals.

Stimulus properties of PMMA: effect of optical isomers and conformational restriction.
Young R, Dukat M, Malmusi L, Glennon RA.
Pharmacol Biochem Behav. 1999 Oct;64(2):449-53.

para-Methoxymethamphetamine (PMMA), a structural hybrid of two central stimulants, lacks stimulant properties but behaves in a manner similar to that of MDMA [N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane]. PMMA has been established as a training drug in drug discrimination studies, and in the present investigation we sought to determine which optical isomer of PMMA is primarily responsible for its stimulus effects. Because PMMA is a conformationally flexible molecule, it was also of interest to determine what conformation is most important for its actions., Accordingly, we prepared and examined S(+)PMMA, R(−)PMMA, and conformationally restricted forms of PMMA: PMMA-AT, TIQ-1, and TIQ-2. S(+)PMMA (ED50 = 0.32 mg/kg) was found to be at least as potent as PMMA (ED50 = 0.41 mg/kg), whereas R(−)PMMA failed to result in complete stimulus generalization. An aminotetralin-like conformation, as found in PMMA-AT (ED50 = 0.29 mg/kg), seems to better account for the actions of PMMA than a tetrahydroisoquinoline-like conformation because TIQ-1 and TIQ-2 failed to result in stimulus generalization. The results of the present study further support the concept that PMMA and MDMA share considerable similarity with respect to their stimulus properties in animals except that PMMA lacks the amphetaminergic stimulant component of action associated with MDMA.

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.
Young R, Gabryszuk M, Glennon RA.
Pharmacol Biochem Behav. 1998 Oct;61(2):169-73.

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (−)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (−)ephedrine and caffeine, which produced <<1% drug-appropriate responding when administered alone, were able to enhance each other’s stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose–response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (−)ephedrine and caffeine may mutually potentiate one another’s stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Discriminative stimulus properties of (-)ephedrine.
Young R, Glennon RA.
Pharmacol Biochem Behav. 1998 Jul;60(3):771-5.

Ephedrine, a structural analog of methamphetamine, is one of the major constituents of legally available herbal dietary supplements. Although racemic ephedrine and ephedra extract have been previously used as training drugs in drug discrimination studies, there is evidence that the two optical isomers of ephedrine do not produce identical amphetamine-like stimulus effects in rats. Consequently, we trained a group of six male Sprague–Dawley rats to discriminate 4 mg/kg of the more potent optical isomer of ephedrine, (−)ephedrine, from saline vehicle. The (−)ephedrine stimulus (ED50 = 0.8 mg/kg) generalized to other central stimulants such as S(+)amphetamine (ED50 = 0.4 mg/kg), cocaine (ED50 = 2.7 mg/kg), methylphenidate (ED50 = 1.2 mg/kg), S(−)methcathinone (ED50 = 0.3 mg/kg), and caffeine (ED50 = 36.7 mg/kg), but stimulus generalization failed to occur to either S(+)methamphetamine or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA). In addition, although we have previously shown that a (+)amphetamine stimulus generalizes to (−)ephedrine but not to (+)ephedrine, in the present investigation the (−)ephedrine stimulus generalized to (+)ephedrine (ED50 = 2.6 mg/kg). From the findings (a) that (−)ephedrine is approximately 10 times less potent than (+)amphetamine in (+)amphetamine-trained rats, whereas it is only half as potent as (+)amphetamine in (−)ephedrine-trained animals; (b) that the (−)ephedrine stimulus failed to generalize to (+)methamphetamine; and (c) that the (−)ephedrine stimulus generalized to (+)ephedrine, it is concluded that the stimulus effects of (+)amphetamine and (−)ephedrine as training drugs, while similar, are not identical. It is also concluded that the stimulus effects of (−)ephedrine and those of the designer drug MDMA, while perhaps sharing some amphetaminergic commonality, are nonidentical.

Initial characterization of PMMA as a discriminative stimulus.
Glennon RA, Young R, Dukat M, Cheng Y.
Pharmacol Biochem Behav. 1997 May-Jun;57(1-2):151-8.

The phenylisopropylamine PMMA or N-methyl-1-(4-methoxyphenyl)-2-aminopropane, a structural hybrid of paramethoxyamphetamine (PMA) and methamphetamine, has been previously shown to unexpectedly lack amphetamine-like or hallucinogen-like stimulus properties in animals. For example, in tests of stimulus generalization, neither a (+)amphetamine stimulus nor a DOM stimulus generalized to PMMA. It has also been shown, however, that stimulus generalization does occur in animals trained to discriminate the designer drug MDMA ("Ecstasy" or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane) from vehicle. In order to further characterize this unique agent, we trained a group of six Sprague-Dawley rats to discriminate 1.25 mg/kg of PMMA (ED50 = 0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalize to the phenylisopropylamine stimulant (+)amphetamine, or to the phenylisopropylamine hallucinogen DOM. Stimulus generalization occurred to (+/-)MDMA (ED50 = 1.32 mg/kg) and S(+)MDMA (ED50 = 0.48 mg/kg). Partial generalization occurred with R(+)MDMA, PMA, 3.4-DMA, and fenfluramine. The PMMA stimulus also generalized to the alpha-ethyl homolog of PMMA (EH/PMMA, ED50 = 1.29 mg/kg). Taken together, the results of these studies suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA. These findings support our previous suggestion that PMMA be considered the structural parent of the MDMA-like family of designer drugs.

Cocaine-stimulus generalization to MDA optical isomers: a reevaluation.
Young R, Glennon RA.
Pharmacol Biochem Behav. 1997 May-Jun;57(1-2):115-8.

It has already been demonstrated that the psychoactive agent 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) produces effects that are both hallucinogen-like and amphetamine- or stimulant-like in animals. Hallucinogenic activity is associated primarily with the R(−)-isomer of MDA whereas stimulant activity is primarily associated with the S(+)-isomer. Because a previous report indicates that S(+)MDA fails to substitute for cocaine in rats trained to discriminate cocaine from vehicle, and because these findings are inconsistent with the purported stimulant nature of S(+)MDA, we reinvestigated the effect of both MDA isomers in rats. In this investigation, S(+)MDA doses of 1.25 and 1.5 mg/kg were found to produce > 80% cocaine-appropriate responding in rats trained to discriminate 8 mg/kg of cocaine from saline. However, consistent with a previous report, R(−)MDA resulted only in partial generalization. These new results support the hypothesis that the optical isomers of MDA produce distinguishable stimulus effects in rats, and that S(+)MDA is the more stmulant isomer of MDA.

Clobenzorex: evidence for amphetamine-like behavioral actions.
Young R, Darmani NA, Elder EL, Dumas D, Glennon RA.
Pharmacol Biochem Behav. 1997 Feb;56(2):311-6.

Clobenzorex, an optically active N-substituted derivative of (+)amphetamine, has been identified on the illicit market. Because so little is known regarding the pharmacology or abuse potential of this agent, it was examined in tests of stimulus generalization in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle to determine if it would produce amphetamine-appropriate responding. Clobenzorex (ED50 = 6.6 mg/kg) substituted for (+)amphetamine (ED50 = 0.3 mg/kg) but was approximately twenty times less potent than the training drug. Clobenzorex was also compared with (+)amphetamine and cocaine for its ability to induce locomotor stimulation and rearing frequency in mice. Clobenzorex was active in both assays but was less potent than either (+)amphetamine or cocaine. It is concluded that, although weaker than (+)amphetamine, clobenzorex constitutes an agent with amphetamine-like central stimulant behavioral properties.

Methcathione ("cat"): an enantiomeric potency comparison.
Glennon RA, Young R, Martin BR, Dal Cason TA.
Pharmacol Biochem Behav. 1995 Apr;50(4):601-6.

With regard to its chemical structure, methcathinone is to cathinone what methamphetamine is to amphetamine. Although it is a drug of abuse outside the United States, methcathinone is only recently making an appearance on the clandestine market in this country and has just been classified a Schedule I substance under the Emergency Scheduling Act. We have previously demonstrated that racemic methcathinone produces locomotor stimulation in mice, and substitutes for cocaine and (+)amphetamine in rats trained to discriminate either cocaine or (+)amphetamine, respectively, from saline in tests of stimulus generalization. Because an enantiomeric potency comparison has never been reported for the optical isomers of methcathinone, in the present investigation we synthesized samples of S(−)- and R(+)methcathinone and compared them for their ability: a) to produce locomotor stimulation in mice, b) to elicit cocaine-like responding in rats trained to discriminate 8.0 mg/kg of cocaine from saline vehicle, and c) to elicit (+)-amphetamine-appropriate responding in rats trained to discriminate 1.0 mg/kg of (+)amphetamine from saline vehicle. S(−)Methcathinone was about twice as potent as S(+)amphetamine and three to five times more potent than R(+)methcathinone in the three pharmacologic assays. We conclude that both optical isomers possess central stimulant character, but that S(−)methcathinone is somewhat more potent than R(+)methcathinone.

Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex.
Young R, Glennon RA.
Pharmacol Biochem Behav. 1993 May;45(1):229-31.

Rats were trained to discriminate 8 mg/kg cocaine from saline vehicle for the purpose of examining the stimulus properties of two novel and structurally related drugs of abuse recently confiscated on the illicit market: (+/-)methcathinone and cis(+/-)4-methylaminorex. The stimulus properties of these controlled substance analogs were compared with those of their parent compounds (+/-)cathinone and aminorex, respectively. All agents resulted in cocaine-stimulus generalization with the following rank order of potency: aminorex (ED50 value = 0.8 microM/kg) > methcathinone (1.9 microM/kg) > cathinone (3.7 microM/kg) > 4-methylaminorex (5.2 microM/kg) > cocaine (7.6 microM/kg).

Further studies on N-methyl-1(3,4-methylenedioxyphenyl)-2-aminopropane as a discriminative stimulus: antagonism by 5-hydroxytryptamine3 antagonists.
Glennon RA, Higgs R, Young R, Issa H.
Pharmacol Biochem Behav. 1992 Dec;43(4):1099-106.

Investigation of MDMA-related agents in rats trained to discriminate MDMA from saline.
Glennon RA, Higgs R.
Pharmacol Biochem Behav. 1992 Nov;43(3):759-63.

7is
(Hive Bee)
06-10-04 10:43
No 512563
User Picture       All the missing PBB articles part 4
(Rated as: excellent)

Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine.
Herndon JL, Pierson ME, Glennon RA.
Pharmacol Biochem Behav. 1992 Nov;43(3):739-48.

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.

Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh").
Glennon RA, Misenheimer B.
Pharmacol Biochem Behav. 1990 Mar;35(3):517-21.

Like other phenylisopropylamine derivatives, 4-methylaminorex is a central stimulant. The cis isomer of 4-methylaminorex ("U4Euh"; "ICE") has appeared on the clandestine market as a novel designer drug and was recently classified as a Schedule I substance. In the present investigation, the stimulus properties of racemic cis, racemic trans, and all four individual optical isomers of 4-methylaminorex were examined in rats trained to discriminate 1 mg/kg of S(+)amphetamine sulfate from saline. The S(+)amphetamine stimulus generalized to all of the agents investigated and the relative potencies of the optical isomers (followed by ED50 values) were as follows:trans(4S,5S) (0.25 mg/kg) > cis(4S,5R) (1.2 mg/kg) = cis(4R,5S) (1.5 mg/kg) > trans(4R, 5R). The trans(4R,5R) isomer did not completely substitute for S(+)amphetamine unless a longer (i.e., 60-min) presession injection interval was used, suggesting that it has a longer duration of onset that the other isomers of 4-methylaminorex. The results, which are consistent with established structure-activity relationships, suggest that the trans(4S,5S) isomer (which has not been scheduled) is similar in potency to (+)amphetamine (ED50=0.4 mg/kg) and is more potent than either of the cis isomers.

Stimulus effects of N-monoethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDE) and N-hydroxy-1-(3,4-methylenedioxyphenyl)-2-aminopropane (N-OH MDA) in rats trained to discriminate MDMA from saline.
Glennon RA, Misenheimer BR.
Pharmacol Biochem Behav. 1989 Aug;33(4):909-12.

Tests of stimulus generalization were conducted using rats trained to discriminate 1.5 mg/kg of N-monomethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane HCl (MDMA) from saline in order to determine if two structurally related analogs (MDE and N-OH MDA) would produce similar stimulus effects. The MDMA-stimulus (MDMA, ED50 value = 0.76 mg/kg) generalized both to MDE (ED50 value = 0.73 mg/kg) and N-OH MDA (ED50 value = 0.47 mg/kg). Administration of (+)amphetamine resulted in partial generalization (maximum of 49% MDMA-appropriate responding) in the MDMA-trained animals. Taken together with our previous studies showing that MDMA substitutes for the phenylisopropylamine stimulant (+)amphetamine, but that neither MDE nor N-OH MDA substitute for (+)amphetamine or for the phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), the present results [i.e., MDMA-stimulus generalization to MDE, N-OH MDA, but not to (+)amphetamine] suggest that 1) MDMA produces effects other than those that may be considered amphetamine-like, and 2) MDE and N-OH MDA are MDMA-like agents with even less of an amphetamine-like component of action than MDMA itself.

A preliminary behavioral investigation of PMMA, the 4-methoxy analog of methamphetamine.
Glennon RA, Ismaiel AE, Martin B, Poff D, Sutton M.
Pharmacol Biochem Behav. 1988 Sep;31(1):9-13.

The controlled-substance analog N-monomethyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) may be viewed as being either the 4-methoxy analog of methamphetamine or the N-methyl analog of 1-(4-methoxyphenyl)-2-aminopropane (PMA). Because of its abuse potential, PMMA was examined with regard to (a) its stimulus properties in rats trained to discriminate either 1.0 mg/kg of (+)amphetamine or (±)DOM from saline, (b) its toxicity (isolated and aggregated) in mice relative to (±)PMA, and (c) its locomotor stimulant activity in mice relative to (±)amphetamine, (±)methamphetamine, and (±)PMA. Racemic PMMA produced neither DOM-like nor, unlike PMA, amphetamine-like stimulus effects. There was no significant difference between the 24-hr isolated (LD50=63 mg/kg) and aggregated (LD50=53 mg/kg) toxicity, and PMMA did not produce significant locomotor stimulation at doses of up to 30 mg/kg. The present results suggest that while PMMA may produce central effects it does not appear to behave as a simple amphetamine-like agent.

Stimulus properties of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs.
Glennon RA, Yousif M, Patrick G.
Pharmacol Biochem Behav. 1988 Mar;29(3):443-9.

Using a standard two-lever operant procedure, groups of rats were trained to discriminate intraperitoneal doses of the phenylisopropylamines (+)amphetamine (1.0 mg/kg) or racemic 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 1.0 mg/kg) from saline using a VI 15-sec schedule of reinforcement for food reward. Once trained, the animals were administered doses of several methylenedioxy analogs (MDAs) of phenylisopropylamine including the N-monomethyl [S(+)MDMA and R(−)MDMA], N-monoethyl [(±)MDE, S(+)MDE, and R(−)MDE], and the N-hydroxyl [(±)N---OH MDA] derivatives. The DOM-stimulus did not generalize to any of these agents. The amphetamine-stimulus generalized to S(+)MDMA, S(+)N-ethylamphetamine and (±)N-hydroxyamphetamine, but not to R(−)MDMA, (±)MDE,S(+)MDE, R(−)MDE, or N---OH MDA. The present results are consistent with other reports in the literature suggesting that the psychoactive effects of certain MDA derivatives may be other than simply amphetamine- or DOM-like.

The effect of MDA and MDMA ("Ecstasy") isomers in combination with pirenpirone on operant responding in mice.
Rosecrans JA, Glennon RA.
Pharmacol Biochem Behav. 1987 Sep;28(1):39-42.

The behaviorally disruptive effects of the optical isomers of 1-(3,4-methylenedioxyphenyl-2-aminopropane) (MDA) and its N-methyl derivative (MDMA) were evaluated in 27 mice trained to bar-press for a liquid food reinforcement. In addition, a second study was conducted in which mice were pretreated with either saline or the 5-HT-2 antagonist, pirenpirone, prior to the administration of either MDMA or MDA using the same behavioral procedure. The results indicated that the behaviorally disruptive effects produced only by R(−)-MDA, but not those of S(+)-MDA, R(−)-MDMA, nor of S(+)-MDMA, were significantly attenuated by pirenpirone. These findings support previous research findings which indicate that this isomer may be producing its behaviorally disruptive effects via an action on 5-HT-2 receptors.

Methcathinone: a new and potent amphetamine-like agent.
Glennon RA, Yousif M, Naiman N, Kalix P.
Pharmacol Biochem Behav. 1987 Mar;26(3):547-51.

The purpose of the present investigation was to examine the effect of N-monomethylation of phenylisopropylamine derivatives on amphetamine-like activity. In tests of stimulus generalization using rats trained to discriminate 1.0 mg/kg of (+)-amphetamine from saline, the N-monomethyl derivatives of 1-(X-phenyl)-2-aminopropane, where X=2,4-dimethoxy (2,4-DMA), 3,4-dimethoxy (3,4-DMA), 2,4,5-trimethoxy (2,4,5,-TMA), and 2-methoxy-4,5-methylenedioxy (MMDA-2), did not produce amphetamine-appropriate responding at the doses evaluated. However, the N-monomethyl derivative of cathinone (i.e., methcathinone), like cathinone, resulted in stimulus generalization. Further studies with this agent revealed that (a) in the amphetamine-trained animals, methcathinone (ED50=0.37 mg/kg) is more potent than racemic cathinone or racemic amphetamine (ED50=0.71 mg/kg in both cases), (b) methcathinone is capable of inducing release of radioactivity from [3H]dopamine -prelabeled tissue of rat caudate nucleus in a manner similar to that observed with cathinone, amphetamine, and methamphetamine, and (c) methcathinone is more potent than cathinone as a locomotor stimulant in mice as determined by their effect on spontaneous activity. The results of the present study provide evidence for a structural analogy between the prototypic psychostimulants amphetamine/methamphetamine and cathinone/methcathinone, and lend further support to the concept that amphetamine and cathinone correspond in their pharmacological effects.

The effect of MDMA ("Ecstasy") and its optical isomers on schedule-controlled responding in mice.
Glennon RA, Little PJ, Rosecrans JA, Yousif M.
Pharmacol Biochem Behav. 1987 Feb;26(2):425-6.

Eleven mice were trained to respond under an FR 20 schedule of reinforcement and, after learning the schedule, were administered doses of saline and the following phenylisopropylamines: (±)-MDMA, S(+)-MDMA, R(−)-MDMA and (+)-amphetamine. Each of the phenylisopropylamines decreased rates of operant responding in a dose-dependent manner. S(+)-MDMA (ED50=3.1 mg/kg) was nearly equipotent with racemic MDMA and four times more potent than R(−)-MDMA (ED50=4.1 and 11.6 mg/kg, respectively), but less potent than (+)-amphetamine (ED50=0.74 mg/kg). The present study constitutes the first enantiometric behavioral-potency comparison for the optical isomers of MDMA.

Cathinone, cocaine and methamphetamine: similarity of behavioral effects.
Schechter MD, Glennon RA.
Pharmacol Biochem Behav. 1985 Jun;22(6):913-6.

The discriminative stimulus properties of (±)-cathinone were tested by training eight rats to discriminate between the interoceptive cues produced by 0.6 mg/kg (±)-cathinone and saline in a food-reinforced, two lever operant task. Doses of cocaine and methamphethamine were observed to tranfer to the cathinone cue and all three drugs exhibited decreased discriminative performance with decreasing doses. The ED50 for (±)-cathinone, (±)-methamphetamine and cocaine were 0.23, 0.17, and 1.97 mg/kg, respectively, and the three curves were shown to be parallel. These data indicate the possibility of a common mechanism/site of action for these three stimulants, presumably by their actions upon central dopaminergic neurons.

Discriminative stimulus properties of S(-)- and R(+)-cathinone, (+)-cathine and several structural modifications.
Glennon RA, Schechter MD, Rosecrans JA.
Pharmacol Biochem Behav. 1984 Jul;21(1):1-3.

Rats trained to discriminate between the stimulus properties of 0.6 mg/kg of racemic cathinone and its vehicle, in a two-lever operant task for food reinforcement, were administered doses of S(-)-cathinone, R(+)-cathinone, (+)-cathine and several structurally-related derivatives, in order to study structure-activity relationships. The optical isomers of cathinone and (+)-cathine produced patterns of responding similar to that observed with the training drug; S(-)-cathinone (ED50 = 0.22 mg/kg) was the more active of the two isomers, while R(+)-cathinone (ED50 = 0.72 mg/kg) was more active than (+)-cathine (ED50 = 1.61 mg/kg). In contrast, removal of the alpha-methyl group of cathinone, or substitution at the 4-position of racemic cathinone by a hydroxyl, methoxyl or chloro group, essentially abolished activity at dose levels comparable to the training dose of cathinone.

Similarity between (+)-amphetamine and amfonelic acid.
Aceto MD, Rosecrans JA, Young R, Glennon RA.
Pharmacol Biochem Behav. 1984 Apr;20(4):635-7.

Rats, trained to discriminate the CNS stimulant (+)-amphetamine (1.0 mg/kg) from saline in a two-lever drug administration task, were challenged with various doses of the structurally dissimilar CNS stimulant amfonelic acid. Amfonelic acid was found to substitute for the amphetamine stimulus and was found to be 1.5 times more potent than amphetamine.

7is
(Hive Bee)
06-10-04 11:10
No 512565
User Picture       All the missing PBB articles part 5
(Rated as: excellent)

Further investigation of the discriminative stimulus properties of MDA.
Glennon RA, Young R.
Pharmacol Biochem Behav. 1984 Apr;20(4):501-5.

Rats trained to discriminate either (+)-amphetamine or (±)-MDA from saline in a two-lever drug discrimination task, were use to study the stimulus effects of MDA and its two optical isomers. Amphetamine-stimulus generalization occurred to S(+)-MDA, but not to its enantiomer R(−)-MDA. This, coupled with our earlierfinding of DOM-stimulus generalization to R(−)-MDA but not to S(+)-MDA, suggests that the stimulus effects of S(+)-MDA are predominantly amphetamine-like while those of R(−)-MDA are more DOM-like. Thus, animals trained to discriminate racemic MDA from saline can apparently recognize members of both classes of agents.

Comparison of behavioral effects of cathinone, amphetamine and apomorphine.
Schechter MD, Rosecrans JA, Glennon RA.
Pharmacol Biochem Behav. 1984 Feb;20(2):181-4.

Rats were trained to discriminate between the stimulus properties of 0.6 mg/kg ±-cathinone and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower cathinone doses and analysis of the dose-response curve indicated an ED50 of 0.24 mg/kg. Administration of 0.2–0.8 mg/kg d-amphetamine produced a pattern of responding similar to that observed with cathinone. The dose-response curve after d-amphetamine was shown to be parallel to that of cathinone and the ED50 generated was 0.21 mg/kg. Thus, cathinone was equi-potent to d-amphetamine in this behavioral paradigm. In contrast, administration of 0.16–0.32 mg/kg apomorphine produced intermediate results. The results suggest a common site and/or mechanism for action of ±-cathinone and d-amphetamine.

(-)PPAP: a new and selective ligand for sigma binding sites.
Glennon RA, Battaglia G, Smith JD.
Pharmacol Biochem Behav. 1990 Nov;37(3):557-9.

Most agents employed for the investigation of sigma (sigma) binding sites display relatively low affinity for these sites, bind both at sigma sites and at either phencyclidine (PCP) sites or dopamine receptors with similar affinity, and/or produce some dopaminergic activity in vivo. We describe a new agent, (-)PPAP or R(-)-N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane hydrochloride, that binds with high affinity and selectivity at sigma (IC50 = 24 nM) versus either PCP sites (IC50 greater than 75,000 nM) or D1 and D2 dopamine receptors (IC50 greater than 5,000 nM). The sigma affinity of this agent is comparable to that of the standard ligands (+)-3-PPP and DTG. Furthermore, although (-)PPAP is structurally related to amphetamine, it neither produces nor antagonizes amphetamine-like stimulus effect in rats trained to discriminate 1 mg/kg of S(+)amphetamine from saline.

Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.
Glennon RA, Young R, Herndon JL.
Pharmacol Biochem Behav. 1993 Aug;45(4):865-9.

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

Stimulus properties of tiflucarbine: a novel antidepressant agent.
Glennon RA, De Vry J, Spencer DG Jr, Glaser T.
Pharmacol Biochem Behav. 1990 Dec;37(4):769-71.

Tiflucarbine is a structurally novel antidepressant that binds at central serotonin (5-HT) binding sites. There is also evidence that this agent is both a 5-HT1 and a 5-HT2 agonist. To further characterize the serotonergic actions of this agent, tiflucarbine was evaluated in groups of rats trained to discriminate the 5-HT1A agonist 8-OH DPAT, the 5-HT2 agonist DOM, and the nonselective 5-HT agonist 5-OMe DMT from saline. Tiflucarbine resulted in partial generalization in the DOM-trained and in the 8-OH DPAT-trained animals. Although two-thirds of the animals were disrupted, 10 mg/kg of tiflucarbine resulted in stimulus generalization in the 5-OMe DMT-trained animals. It is concluded that tiflucarbine is most likely a nonselective 5-HT agonist.

Stimulus generalization of 1-(3-trifluoromethylphenyl)piperazine (TFMPP) to propranolol, pindolol, and mesulergine.
Glennon RA, Pierson ME, McKenney JD.
Pharmacol Biochem Behav. 1988 Jan;29(1):197-9.

Using standard operant procedures with rats trained to discriminate the serotonin (5-HT) agonist 1-(-3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus generalization and stimulus antagonism were conducted with propranolol, pindolol, and mesulergine. Neither propranolol nor mesulergine antagonized the TFMPP stimulus (pindolol was not evaluated as an antagonist). However, TFMPP-stimulus generalization occurred with all three agents. These results suggest that the TFMPP-stimulus may involve both a 5-HT1B and a 5-HT1C mechanism and further suggest that propranolol, pindolol, and mesulergine may be capable of acting as agonists at certain populations of serotonin receptors.

Rhodium
(Chief Bee)
09-08-04 22:49
No 530378
User Picture       Glennon:The study of SAR using drug discrimination

Richard A. Glennon & Richard Young., The study of structure-activity relationships using drug discrimination methodology. (http://www.addictionscience.net/MARPADc18.htm)
Chapter 18 in Methods of Assessing the Reinforcing Properties of Abused Drugs M.A. Bozarth (ed.), Springer-Verlag, New York (1987)

I assume this corresponds to item #8 in the publication list at http://www.pharmacy.vcu.edu/glennon/cv.htm#BookChapters

This and all other chapters of the above book are available in Post 530376 (Rhodium: "E-Book: Assessing Drugs Reinforcing Properties", General Discourse)

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