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All 18 posts Subject: Interesting article on cocaine analogues pharm. Please login to post Down

Bandil
(Hive Bee)
04-24-03 12:31
No 429127
      Interesting article on cocaine analogues pharm.

Abstract

Abnormal dopamine signaling in brain has been implicated in several conditions such as cocaine abuse, Parkinson's disease and depression. Potent and selective dopamine transporter inhibitors may be useful as pharmacological tools and therapeutic agents. Simple substituted pyridines were discovered as novel dopamine transporter (DAT) inhibitors through pharmacophore-based 3D-database search. The most potent compound 18 has a Ki value of 79 nM in inhibition of WIN35,248 binding to dopamine transporter and 255 nM in inhibition of dopamine reuptake, respectively, as potent as cocaine. Preliminary structure–activity relationship studies show that the geometry and the nature of the substituents on the pyridine ring determine the inhibitory activity and selectivity toward the three monoamine transporters. The substituted pyridines described herein represent a class of novel DAT inhibitors with simple chemical structures and their discovery provides additional insights into the binding site of DAT.

fulltext found at:

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF9-47HS401-1&_user=45981&_handle=W-WA-A-A-ZB-MsSAYVA-UUA-AUCAWCWCAE-BWWWYUUZB-ZB-U&_fmt=full&_coverDate=02%2F10%2F2003&_rdoc=44&_orig=browse&_srch=%23toc%235221%232003%23999869996%23383413!&_cdi=5221&view=c&_acct=C000004938&_version=1&_urlVersion=0&_userid=45981&md5=720d25cb8d63d5ee4bad8cc5e5af50ab

edit: sorry about the ugly format the link is supplied in. Just copy-paste it into the browser. I just couldn't get it to show it right. If any mods know how please edit my post :)

Cops are not there to help you, they're there to bust you.

Lilienthal
(Moderator)
04-24-03 14:53
No 429142
User Picture       why not use the doi number?

Typing "[doi]10.1016/S0960-894X(02)00943-5[/doi]" leads you to the very same place: DOI:10.1016/S0960-894X(02)00943-5

Rhodium
(Chief Bee)
04-24-03 23:43
No 429220
User Picture       Bioorg Med Chem Lett 13, 513-517 (2003)

Bioorganic& Medicinal Chemistry Letters 13 (2003) 513–517 (https://www.rhodium.ws/pdf/pyridine.dat-inhibitors.pdf)

slappy
(Hive Addict)
04-26-03 13:26
No 429543
      18 + 233

I think that compound 23 looks the most interestin. It has a DA/5HT/NE profile closer to that of cocaine, while 18 is only as "potent" as cocaine with respect to DAT binding, and WIN35,248 competative binding assay.

Compound 18 is available from chem suppliers for ~$5/g. Compound 23 can be made in one step from the obvious and cheap starting materials.

Bandil
(Hive Bee)
04-26-03 14:09
No 429553
      Has anyone here on the-hive bioassayed compund

Has anyone here on the-hive bioassayed compund num. 18? If it's dirt cheap, theres no reason not to :)

Cops are not there to help you, they're there to bust you.

Lego
(Hive Bee)
12-08-03 23:08
No 475506
User Picture       3D-QSAR of cocaine binding by a human antibody
(Rated as: good read)

J. Med. Chem., ASAP Article

DOI:10.1021/jm030351z
Fulltext (http://lego.chemistry.tripod.com/cocaineQSAR.html)

Web Release Date: December 3, 2003

Three-Dimensional Quantitative Structure-Activity Relationship Modeling of Cocaine Binding by a Novel Human Monoclonal Antibody

Stefan Paula, Michael R. Tabet, Carol D. Farr, Andrew B. Norman, and W. James Ball, Jr.*

Department of Pharmacology and Cell Biophysics and Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0575

Received July 24, 2003

Abstract:

Human monoclonal antibodies (mAbs) designed for immunotherapy have a high potential for avoiding the complications that may result from human immune system responses to the introduction of nonhuman mAbs into patients. This study presents a characterization of cocaine/antibody interactions that determine the binding properties of the novel human sequence mAb 2E2 using three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology. We have experimentally determined the binding affinities of mAb 2E2 for cocaine and 38 cocaine analogues. The K_d of mAb 2E2 for cocaine was 4 nM, indicating a high affinity. Also, mAb 2E2 displayed good cocaine specificity, as reflected in its 10-, 1500-, and 25000-fold lower binding affinities for the three physiologically relevant cocaine metabolites benzoylecgonine, ecgonine methyl ester, and ecgonine, respectively. 3D-QSAR models of cocaine binding were developed by comparative molecular similarity index analysis (CoMSIA). A model of high statistical quality was generated showing that cocaine binds to mAb 2E2 in a sterically restricted binding site that leaves the methyl group attached to the ring nitrogen of cocaine solvent-exposed. The methyl ester group of cocaine appears to engage in attractive van der Waals interactions with mAb 2E2, whereas the phenyl group contributes to the binding primarily via hydrophobic interactions. The model further indicated that an increase in partial positive charge near the nitrogen proton and methyl ester carbonyl group enhances binding affinity and that the ester oxygen likely forms an intermolecular hydrogen bond with mAb 2E2. Overall, the cocaine binding properties of mAb 2E2 support its clinical potential for development as a treatment of cocaine overdose and addiction.

The candle that burns twice as bright burns half as long

silenziox
(Hive Bee)
12-09-03 13:22
No 475625
      18 & 23 Cas numbers???

For the bees whose pdf-viewer crashes the computer:

Molecule: 18 = 4-benzhydrylpyridine ("C(c1ccncc1)(c2ccccc2)c3ccccc3") Molecule: 23 = 4-(1,2-diphenylethyl)pyridine ("C(c1ccccc1)C(c2ccncc2)c3ccccc3")

What might be the cas numbers for these? I'm pretty sure that searching for "4-benzhydrylpyridine" will not yield anything wink

Edit: It's best to search with diphenyl-4-pyridylmethane or with 4-(Diphenylmethyl)pyridine.. CAS Number is 3678-72-6. Ten grams of this stuff sells for slightly over 80EUR.

The MSDS says it's irritating to eyes, respiratory system and skin. Decomposition products are CO, CO2 and nitrogen oxides. Not suitable for smoking then (MP 124-126°C)..

Anyway, physical properties:

18
C18H15N
MW 245.318
Density 1.085
H³WIN binding 0.079 +/- 0.004
H³DA uptake 0.255 +/- 0.008
H³5-HT uptake 1.160 +/- 0.020
H³NE uptake 3.46 +/- 0.10

23
C19H17N
MW 259.345
Density 1.080
H³WIN binding 0.099 +/- 0.017
H³DA uptake 0.263 +/- 0.003
H³5-HT uptake 0.910 +/- 0.100
H³NE uptake 3.93 +/- 0.008

Cocaine's binding & uptake affinity values are following:
H³DA uptake 0.270 +/- 0.020
H³5-HT uptake 0.155 +/- 0.001
H³NE uptake 0.108 +/- 0.004

The best position is the next position

silenziox
(Hive Bee)
12-09-03 18:15
No 475662
      I think that slappy confused that "dirt...

I think that slappy confused that "dirt cheap chemicalnumber 18" to Diphenyl-2-pyridylmethane [cas#3678-70-4], which indeed cost approx $5 per gram. It's the compound no. 22 in the letter and it has got following properties:

C18H15N
MW 245.3232
MP 59-62°C (suitable for smoking?)
H³WIN binding affinity 0.742 +/- 0.026
H³DA uptake affinity 1.067 +/- 0.034
H³5-HT uptake affinity 35.00 +/- 7.000
H³NE uptake affinity 5.53 +/- 045

The text claims that this compound is 10-fold less potent in WIN binding and 4-fold less potent in inhibition of DA reuptake compared to compound no 18.

The best position is the next position

scarmani
(Hive Bee)
12-10-03 07:00
No 475884
User Picture       More Cocaine Analogs

Synthesis, Monoamine Transporter Binding Properties, and Behavioral Pharmacology of a Series of 3-(Substituted phenyl)-2-(3'-substituted isoxazol-5-yl)tropanes

DOI:10.1021/jm030453p

F. Ivy Carroll, Neil Pawlush, Michael J. Kuhar, Gerald T. Pollard, and James L. Howard
J. Med. Chem.; 2003; ASAP Web Release Date: 09-Dec-2003

Abstract:

Several 3-(substituted phenyl)-2-(3-substituted isoxazol-5-yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC50 values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED50 values for 2-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3-(4-methylphenyl)-2-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3-(4-methylphenyl)-2-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED50values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3-(substituted phenyl)-2-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.

Fulltext: http://www.streamload.com/scarmani/Cocaine/Potent_Isoxazole_Substituted_Cocaine_Analogs_Active_In_Vivo.pdf
Chemistry: http://www.streamload.com/scarmani/Cocaine/Potent_Isoxazole_Substituted_Cocaine_Analogs_Active_In_Vivo_Chemistry.pdf

And a ton of related / semi-related PDF's at http://www.streamload.com/scarmani/Cocaine

Swim has read several posts (eg. by Slappy, Dr_Heckyll) suggesting that various types of DAT inhibitors / cocaine analogs would not have cocaine-like recreational value. On the other hand, swim has also seen several references (eg. posted by Rhodium and pHarmacist) in which cocaine analogs substituted for cocaine in animal discrimination tests, displayed cocaine-like stimulant/locomotor effects, and so on. However, swim has also read that non-euphorigenic compounds (eg. mazindol, apomorphine) have substituted for cocaine in the animal model, or supported self-administration.

All this has left swim a little confused. Swim is wondering, when looking through https://www.rhodium.ws/pdf/cocaineanalogs.pdf, how much is known about in vivo pharmacology of the different structural classes, and which ones have been shown to substitute for cocaine in discriminative stimulus tests.

stop, drop & roll

sushitake
(Hive Bee)
12-10-03 09:37
No 475902
      apomorphine

apomorphine is listed as being a dopamine agonist....I imagine that if it has strong dopamine agonist activity it may also stimulate opiate receptors in the dorsal and ventral striatum where the opiate and dopamine receptors are meshed together.............

opiophile

scarmani
(Hive Bee)
12-10-03 19:20
No 475980
User Picture       Recreational Potential of DAT Inhibs / DA Agonists

Direct DA Agonists?

Swim hasn't seen much discussion of DA agonists at The Hive. (Swim's understanding is that Cocaine is a DAT, 5-HTT and NET inhibitor and VMAT enhancer, whereas Methamphetamine is a DA and NE releaser... but that niether has direct agonist effects at the DA receptor). Because of this, and since there are several DA agonists prescribed for Parkinsons disease, swim assumed they had little or no recreational potential.

For example, swim had always been under the impression that apomorphine had nausea as its primary effect. After doing a quick google search, swim sees it is being sold as an Erectile Dysfunction and Parkinsons medication, with claims that it has a pleasurable effect, promotes secretion of HGH, oxytocin etc. Of course, swim take these claims with a "grain of salt."

Nevertheless, could this suggest that direct DA agonists may have recreational/aphrodesiac potential? If so, there are quite a number of very potent, selective DA agonists for various receptor subtypes.

More Musings on DAT ligands and DARI's

A DAT ligand and DARI, Mazindol is also a prescription drug sold for muscular dystrophy and weight loss. It seems to be a stimulant but not a euphorigenic. (It stimulates beta-adrenergic receptors as well as inhibiting DAT).

Some quotes from the comprehensive https://www.rhodium.ws/pdf/cocaineanalogs.pdf:

"The idea of separability of the binding sites for DA and cocaine on the transporter was first proposed by Rothman in 1990 based on two types of DA reuptake inhibitors: type 1 blockers, which produce euphoria (e.g., cocaine), and type 2 blockers, which are not euphorigenic (e.g., bupropion, nomifensine, benztropine, and mazindol)."

So there are DA reuptake inhibitors which do not produce euphoria. Since swim thought that DA reuptake inhibition was the major component in cocaine's euphoric effects, this is puzzling. Swim was aware that DAT ligands existed which were ineffective at inhibiting DA reuptake, and that these did not have recreational potential... however swim had thought that if the DAT inhibitors were effective DARI's, they would be pleasurable.

Perhaps the type-2 DA reuptake inhibitors (if they indeed do actually inhibit DA reuptake effectively) do not achieve as high extracellular concentrations of DA; or the DARI effects are distributed differently in the brain than cocaine's (by analogy to modafinil vs. amphetamine). Or perhaps SSRI (and/or SNRI) actions of cocaine are crucial to the euphoria.

"Discriminative stimulus properties of cocaine are believed to be modulated by dopamine D1 and D2 receptors in the mesocorticolimbic DA systems."

So presumably agonists at D1 and D2 would substitute for Cocaine in rats, even if they lacked the euphorigenic properties of cocaine.

"The goal of designing cocaine analogues is mainly 3-fold: (1) to modify the chemical structure of cocaine in such a way as to retain or reinforce its useful stimulant or antidepressant pharmacological effects and to minimize its high toxicity and dependence liability, (2) to use high-affinity analogues as pharmacological probes to gain greater insight into the structural requirements for binding to the DAT, and (3) to obtain a competitive cocaine antagonist which can selectively inhibit cocaine binding to the DAT but which itself is devoid of transporter-inhibiting actions and is free from toxic effects. While there has been some success in accomplishing the first two goals, a true cocaine antagonist, which does not elicit stimulant and euphoric behavioral attributes of cocaine, is not known at the present time."

This statement suggests that cocaine analogs which effectively inhibit DA uptake should have, at least to some extent, the stimulant and euphoric attributes of cocaine. And that cocaine analogs which do not inhibit DA uptake do not fully antagonize cocaine.

However, in contrast to this statement, later on in the document it notes: "One of the most promising compounds is GBR 12909 (279; Figure 45). It binds tightly to the DAT and attenuates the increase in extracellular DA level induced by cocaine as measured in the microdialysis experiments.296,297 In addition, it possesses nonstimulant properties in human volunteers298 and is also shown to selectively block cocaine self-administration in rhesus monkey.299 Recently, a derivative of GBR 12909, decanoate 5 (281; Figure 45), has been found to substantially reduce cocaine self-administration in monkeys for nearly a month with only one injection. 300 The mechanism of action of GBR 12909 is considered to be the same as cocaine. It has been suggested that both bind to the same site301 and inhibit the action of DA uptake at the DAT.302 The only difference in the mechanism of action of GBR 12909 and cocaine is that GBR 12909 produces a relatively modest and long-lasting increase in DA, which does not cause the same degree of euphoria compared to cocaine’s burst of pleasure.296,297 Furthermore, the ability of GBR 12909 to block the action of cocaine is derived from its high potency to the DAT ( 500 times greater)."

It seems to swim that cocaine analogs not containing the tropane structure are less likely to have recreational potential... is this a fair summary? Swim would be curious to hear slappy's opinion since he seems most dubious about the recreational potential of many of the cocaine analogs. (Also Dr_Heckyll's, but it seems he has disappeared.)

stop, drop & roll

Rhodium
(Chief Bee)
12-30-03 18:01
No 479807
User Picture       PDF version

Three-Dimensional Quantitative Structure-Activity Relationship Modeling of Cocaine Binding by a Novel Human Monoclonal Antibody
Stefan Paula, Michael R. Tabet, Carol D. Farr, Andrew B. Norman, and W. James Ball, Jr.
J. Med. Chem., 47, 133-142 (2004) (https://www.rhodium.ws/pdf/cocaine.3d-qsar.pdf)
DOI:10.1021/jm030351z S0022-2623(03)00351-0

Abstract
Human monoclonal antibodies (mAbs) designed for immunotherapy have a high potential for avoiding the complications that may result from human immune system responses to the introduction of nonhuman mAbs into patients. This study presents a characterization of cocaine/antibody interactions that determine the binding properties of the novel human sequence mAb 2E2 using three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology. We have experimentally determined the binding affinities of mAb 2E2 for cocaine and 38 cocaine analogues. The Kd of mAb 2E2 for cocaine was 4 nM, indicating a high affinity. Also, mAb 2E2 displayed good cocaine specificity, as reflected in its 10-, 1500-, and 25000-fold lower binding affinities for the three physiologically relevant cocaine metabolites benzoylecgonine, ecgonine methyl ester, and ecgonine, respectively. 3D-QSAR models of cocaine binding were developed by comparative molecular similarity index analysis (CoMSIA). A model of high statistical quality was generated showing that cocaine binds to mAb 2E2 in a sterically restricted binding site that leaves the methyl group attached to the ring nitrogen of cocaine solvent-exposed. The methyl ester group of cocaine appears to engage in attractive van der Waals interactions with mAb 2E2, whereas the phenyl group contributes to the binding primarily via hydrophobic interactions. The model further indicated that an increase in partial positive charge near the nitrogen proton and methyl ester carbonyl group enhances binding affinity and that the ester oxygen likely forms an intermolecular hydrogen bond with mAb 2E2. Overall, the cocaine binding properties of mAb 2E2 support its clinical potential for development as a treatment of cocaine overdose and addiction.

^{The Hive - Clandestine Chemists Without Borders}

xbnmx
(Newbee)
12-31-03 08:53
No 479951
      Are you sure?

So your saying that Diphenyl-2-pyridylmethanehas recreational values equal to that of cocaine?

xbnmx
(Newbee)
01-02-04 10:26
No 480203
      ?

So compund 23 is Triphenylmethylamine aka Tritylamine?

Rhodium
(Chief Bee)
01-03-04 17:56
No 480259
User Picture       tritylamine

Definitely not. Check the structure in the article and compare that with tritylamine shown in http://www.arkat-usa.org/ark/journal/2003/Shine/HS-757J/HS-757J.htm

^{The Hive - Clandestine Chemists Without Borders}

Fastandbulbous
(Stranger)
02-02-04 20:38
No 486081
      anybody bioassayed?

Before anyone gets their hands on any of the pyridine derivitives, I'd like to raise a note of caution. the poor sods who jacked up "new heroin", from a fucked up synthesis of MPPP in the early 80's also dosed themselves with some MPTP ended up with EXTREMLY SEVERE PARKINSONS DISEASE. It appears that the MPTP was metabolized to a 1-methyl-4-phenylpyridinium ion by MAO-B, and this was the agent responsible for destroying the dopamine cells in their substantia nigra (poss irreversable binding causing cell death?). It also came up in a TV program (Horizon - The case of the frozen addict -BBC television) that simple pyridine from car exhausts causes parkinsons when exposed over a long time. See where I'm going?
Before anybody tries any pyridine substituted compound, try and find an in vivo trial of the compound in primates (even if you find one using rats, do not think that it's OK, as MPTP doesn't cause Parkinsons in rodents, just primates, and that includes you and me).
So please be careful with the pyridine derivs., as Parkinsons can really cramp your lifestyle (my grandmother had it during the last few years of her life, and I wouldn't wish it upon anyone).

Rhodium
(Chief Bee)
02-05-04 21:08
No 486652
User Picture       ortho-amino-cocaine 14x more potent
(Rated as: good read)

2'-Substituted analogs of cocaine: Synthesis and dopamine transporter binding potencies
Tarek F. El-Moselhy, Kwasi S. Avora, Garo P. Basmadjiana
Arch. Pharm. Pharm. Med. Chem. 334, 275–278 (2001) (https://www.rhodium.ws/pdf/o-amino-cocaine.pdf)

Abstract
A series of 2'-substituted cocaine analogs (4–8) was prepared and evaluated in an in vitro dopamine transporter (DAT) binding assay. Compounds 4–7 were prepared by esterifying the 3-hydroxyl group of ecgonine methyl ester (3) using the appropriate acid chloride in the presence of Et₃N and benzene. Compound 3 was obtained from cocaine (1) by hydrolysis using 1N HCl to afford ecgonine.HCl which was subjected to acid catalyzed esterification using methanol saturated with HCl gas. Compound 8 was obtained by hydrogenation of 7 using H₂/Pd-C. The IC₅₀ values were calculated from displacement experiment of the radioligand [³H]WIN-35,428 (2). 2'-Aminococaine (8) showed high binding affinity to the DAT (14- and 1.3-fold more active than cocaine and the radioligand 2, respectively). These results, along with previous results, emphasize the importance of a hydrogen-bond donor group at the 2'-position of cocaine to enhance binding affinity to the DAT.

^{The Hive - Clandestine Chemists Without Borders}

Nicodem
(Hive Bee)
10-15-04 15:18
No 535972
User Picture       A cocaine analogs review
(Rated as: excellent)

3beta-(Substituted phenyl)tropan-2-carboxylic Acid Ester Analogues of Cocaine:
Synthesis and Biochemical and Pharmacological Properties
F. Ivy Carroll, Anita H. Lewin, John W. Boja, and Michael J. Kuhar
In: (ed.) Kozikowski, A. Drug Design for Neuroscience (1993) 149-166.

Excerpt:
The effects of more recently synthesized phenyltropane analogs on locomotor activity have revealed that, as expected, RTI-31, RTI-32, RTI-51, and RTI-55 were all significantly more potent than (R)-cocaine. Moreover, the dose that elicited maximal behavioral effects was very similar to the dose that produced maximal occupancy of the transporter binding sites in vivo (61).
Drug discrimination studies have also been carried out (62,63). Balster and coworkers (62) found that RTI-31 and RTI-32, as well as WIN 35,065-2, have (R)-cocaine-like discriminative stimulus effects in rats. WIN 35,065-2 was 14 times re potent than (R)-cocaine while RTI-31 was 26.8 times more potent than (R)-cocaine in vitro and in vivo (44). RTI-32 was only six times more potent than (R)-cocaine (62). Cline et a1. (63) also reported that these analogues substituted for (R)-cocaine in rats trained to discriminate (R)-cocaine from saline. WIN 35,065-2 was 9.7 times more potent than (R)-cocaine, RTI-32 was 6.6 times more potent, and RTI-31 and RTI-55 were 10.3 times and 113.1 times more potent than (R)-cocaine, respectively (63). It is clear that the potency in behavioral studies does not exactly parallel the binding and uptake inhibition studies. Nevertheless, as a group, the more potent compounds in behavior studies tend to be the more potent compounds in binding studies. The reason for this difference is unclear, but it could involve pharmacokinetic differences among the compounds, or it could be also due to differences in pharmacological properties of the different drugs, since these drugs tend to inhibit other neurotransmitter uptake systems as well as possibly have other properties.

“The real drug-problem is that we need more and better drugs.” – J. Ott

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