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All 11 posts Subject: Cocaine analog not found in TFSE Please login to post Down

Jubrail
(Hive Addict)
07-23-03 18:29
No 449302
      Cocaine analog not found in TFSE
(Rated as: good read)

I haven't ever posted in this forum b4, the reason being I don't have enough knowledge. I did find this paper today though (I assume some of you have read it before). It is a more potent analog of cocaine that is discussed in the article. It is not discussed in Beagle's paper on coke analogs, but looks like it would have a relatively similar method of synthesis. Looks incredibly difficult to synth for the typical clandestine chemist, but just hoping to hear what you all have to say about it.

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors
by
Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M,
Johnson KM, Deschaux O, Tella S, Kozikowski AP
Drug Discovery Program,
Institute of Cognitive and Computational Science,
Georgetown University Medical Center,
3970 Reservoir Road, NW,
Washington,
DC 20007-2197, USA.
J Med Chem 2000 Mar 23; 43(6):1215-22

ABSTRACT
The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.

Rainbows & Butterflies Forever :)

Rhodium
(Chief Bee)
07-24-03 05:05
No 449423
User Picture       SAR of piperidine-based cocaine analogs
(Rated as: good read)

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors
Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski AP
J. Med. Chem. 43(6), 1215-22 (2000) (https://www.rhodium.ws/pdf/cocaine.piperidine-based.analogs.sar-2.pdf)

Interesting - this paper is the second part of the infamous one which gives the prep of a potent cocaine analog from arecoline and p-Cl-PhMgBr, described in Post 329686 (Rhodium: "Precious metals & Crack", General Discourse) and the full ref is found in the doc linked in Post 357128 (Rhodium: "Arecocaine", Novel Discourse).

Other Cocaine Analogs:
Post 444618 (Rhodium: "Dopamine Transporter SAR of Tropanes", General Discourse)
Post 440396 (Rhodium: "Novel Sigma-1/DAT ligands", General Discourse)

pericles
(Stranger)
07-24-03 14:48
No 449528
      analogue's effects

It's mentioned Post 212069 (monkpea: "Re: Structurally simple cocaine analogs -Beagle", Novel Discourse) that at least one analogue should produce a numbing effect similar to standard cocaine. Does this hold true for all of them?

I've used TFSE a fair bit, but haven't come up with anything definite - did anyone ever take Rhodium up on his challenge Post 329415 (Rhodium: "I feel there are TOO many coincidences now...", General Discourse)?

It seems like there's a tremendous amount of information about cocaine analogues out there, but no reports of successful (or even, as far as I can tell, attempted synthesis.

Rhodium
(Chief Bee)
07-24-03 16:37
No 449552
User Picture       cocaine analog synthesis attempt

The first cocaine analog synthesis attempt whatsoever I've seen at the Hive is the one posted in Post 446941 (tropine: "Arecoline analogue...freebase success! But....", Serious Chemistry)

Jubrail
(Hive Addict)
07-24-03 21:48
No 449621
      Whew

The arecoline success cheered me greatly. Now, Rhod's challenge I wish I could take up, but I only have the knowledge for basic chem. SWIM has access to 99%+ white. It's unfortunate I wouldn't know how to tell him to do the procedure. Could anybody explain the procedure so that it's somewhere between theory and procedure. SWIM may be willing to play with a small cashwad of white to do this. What is the potency jump supposed to be? Guesses?

Rainbows & Butterflies Forever :)

Rhodium
(Chief Bee)
07-27-03 22:53
No 450252
User Picture       Cocaine to WIN 35,428
(Rated as: good read)

First, you are supposed to turn the cocaine into anhydroecgonine, for example according to the instructions in this article:

An Improved Synthesis of (+)-2-Tropinone
Chunming Zhang, Stacey A. Lomenzo, Charles J. Ballay II, and Mark L. Trudell
J. Org. Chem. 62(22), 7888 - 7889 (1997) (https://www.rhodium.ws/pdf/anhydroecgonine.2-tropinone.pdf)
DOI:10.1021/jo9710083

Then you use that, together with the procedure from the article in Post 221796 (Rhodium: "Re: 4-fluorophenyl cocaine analog", General Discourse), which is a grignard addition of 4-fluorophenylmagnesium bromide to the formed anhydroecgonine (this article also describes the preparation of anhydroecgonine). Have you performed a grignard reaction before?

The 1973 article by Clarke (Post 330321 (Rhodium: "Zorro: The yield minus the losses in each step, ...", General Discourse)) also describes the reaction, and tells us that Compound 13, which is the one we are interested in, is approximately 60x more effective than cocaine on a weight basis to induce "locomotor activity" in mice... To read the *.djvu article in the post above, check out Post 330098 (Rhodium: "What is DejaVu?", General Discourse)

Another 30 para-substituted phenyltropanes made from anhydroecgonine can be found in Table 2, together with binding data here: https://www.rhodium.ws/pdf/cocaineanalogs.pdf

Jubrail
(Hive Addict)
07-27-03 22:58
No 450254
      OK

Honestly, no solid evidence that this is the "supercoke," but sounds like fun, and quite a challenge, I am currently between countries, so it will be a little bit, but with help from a certain bee and some slow reconstruction of my lab in my new residence, I hope to crack this case. Any help is always appreciated.

Rainbows & Butterflies Forever :)

pericles
(Newbee)
07-28-03 22:34
No 450471
      4-fluorophenylmagnesium bromide

As best I know, there's no OTC source for 4-fluorophenylmagnesium bromide. (I'd be quite pleased if someone corrected me) So you'd either be synthing it as well, or ordering it from a chem co. Now, I don't think that'd be a big problem for most people, as as best I know it's not particularly watched. But for those of us who wish to avoid all unwanted attention, it could be a problem.

Rhodium
(Chief Bee)
07-29-03 01:19
No 450491
User Picture       Full procedure patented

The whole procedure from cocaine to the 4-Fluorophenyltropane (including the preparation of the 4-Fluorophenylmagnesium bromide from p-Fluorobromobenzene) can be read on page 14 of Patent EP604354 - but the language is extremely technical.

SilverSurfer
(Hive Bee)
07-29-03 19:40
No 450592
      GrignardQuest

Is that a kind of 1,4 Addition?

The only purpose of your life may be to serve as a warning to others http://www.despair.com

Rhodium
(Chief Bee)
07-29-03 21:43
No 450606
User Picture       Yes, and I know that the details are discussed

Yes, and I know that the details are discussed in another thread on this topic.

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	All 11 posts		Subject: Cocaine analog not found in TFSE		Please login to post		Down


		Jubrail (Hive Addict) 07-23-03 18:29 No 449302				Cocaine analog not found in TFSE (Rated as: good read)
						I haven't ever posted in this forum b4, the reason being I don't have enough knowledge. I did find this paper today though (I assume some of you have read it before). It is a more potent analog of cocaine that is discussed in the article. It is not discussed in Beagle's paper on coke analogs, but looks like it would have a relatively similar method of synthesis. Looks incredibly difficult to synth for the typical clandestine chemist, but just hoping to hear what you all have to say about it. Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors by Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski AP Drug Discovery Program, Institute of Cognitive and Computational Science, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, DC 20007-2197, USA. J Med Chem 2000 Mar 23; 43(6):1215-22 ABSTRACT The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters. Rainbows & Butterflies Forever :)



		Rhodium (Chief Bee) 07-24-03 05:05 No 449423				SAR of piperidine-based cocaine analogs (Rated as: good read)
						Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski AP J. Med. Chem. 43(6), 1215-22 (2000) (https://www.rhodium.ws/pdf/cocaine.piperidine-based.analogs.sar-2.pdf) Interesting - this paper is the second part of the infamous one which gives the prep of a potent cocaine analog from arecoline and p-Cl-PhMgBr, described in Post 329686 (Rhodium: "Precious metals & Crack", General Discourse) and the full ref is found in the doc linked in Post 357128 (Rhodium: "Arecocaine", Novel Discourse). Other Cocaine Analogs: Post 444618 (Rhodium: "Dopamine Transporter SAR of Tropanes", General Discourse) Post 440396 (Rhodium: "Novel Sigma-1/DAT ligands", General Discourse)



		pericles (Stranger) 07-24-03 14:48 No 449528				analogue's effects
						It's mentioned Post 212069 (monkpea: "Re: Structurally simple cocaine analogs -Beagle", Novel Discourse) that at least one analogue should produce a numbing effect similar to standard cocaine. Does this hold true for all of them? I've used TFSE a fair bit, but haven't come up with anything definite - did anyone ever take Rhodium up on his challenge Post 329415 (Rhodium: "I feel there are TOO many coincidences now...", General Discourse)? It seems like there's a tremendous amount of information about cocaine analogues out there, but no reports of successful (or even, as far as I can tell, attempted synthesis.



		Rhodium (Chief Bee) 07-24-03 16:37 No 449552				cocaine analog synthesis attempt
						The first cocaine analog synthesis attempt whatsoever I've seen at the Hive is the one posted in Post 446941 (tropine: "Arecoline analogue...freebase success! But....", Serious Chemistry)



		Jubrail (Hive Addict) 07-24-03 21:48 No 449621				Whew
						The arecoline success cheered me greatly. Now, Rhod's challenge I wish I could take up, but I only have the knowledge for basic chem. SWIM has access to 99%+ white. It's unfortunate I wouldn't know how to tell him to do the procedure. Could anybody explain the procedure so that it's somewhere between theory and procedure. SWIM may be willing to play with a small cashwad of white to do this. What is the potency jump supposed to be? Guesses? Rainbows & Butterflies Forever :)



		Rhodium (Chief Bee) 07-27-03 22:53 No 450252				Cocaine to WIN 35,428 (Rated as: good read)
						First, you are supposed to turn the cocaine into anhydroecgonine, for example according to the instructions in this article: An Improved Synthesis of (+)-2-Tropinone Chunming Zhang, Stacey A. Lomenzo, Charles J. Ballay II, and Mark L. Trudell J. Org. Chem. 62(22), 7888 - 7889 (1997) (https://www.rhodium.ws/pdf/anhydroecgonine.2-tropinone.pdf) DOI:10.1021/jo9710083 Then you use that, together with the procedure from the article in Post 221796 (Rhodium: "Re: 4-fluorophenyl cocaine analog", General Discourse), which is a grignard addition of 4-fluorophenylmagnesium bromide to the formed anhydroecgonine (this article also describes the preparation of anhydroecgonine). Have you performed a grignard reaction before? The 1973 article by Clarke (Post 330321 (Rhodium: "Zorro: The yield minus the losses in each step, ...", General Discourse)) also describes the reaction, and tells us that Compound 13, which is the one we are interested in, is approximately 60x more effective than cocaine on a weight basis to induce "locomotor activity" in mice... To read the .djvu article in the post above, check out Post 330098 (Rhodium: "What is DejaVu?", General Discourse)* Another 30 para-substituted phenyltropanes made from anhydroecgonine can be found in Table 2, together with binding data here: https://www.rhodium.ws/pdf/cocaineanalogs.pdf



		Jubrail (Hive Addict) 07-27-03 22:58 No 450254				OK
						Honestly, no solid evidence that this is the "supercoke," but sounds like fun, and quite a challenge, I am currently between countries, so it will be a little bit, but with help from a certain bee and some slow reconstruction of my lab in my new residence, I hope to crack this case. Any help is always appreciated. Rainbows & Butterflies Forever :)



		pericles (Newbee) 07-28-03 22:34 No 450471				4-fluorophenylmagnesium bromide
						As best I know, there's no OTC source for 4-fluorophenylmagnesium bromide. (I'd be quite pleased if someone corrected me) So you'd either be synthing it as well, or ordering it from a chem co. Now, I don't think that'd be a big problem for most people, as as best I know it's not particularly watched. But for those of us who wish to avoid all unwanted attention, it could be a problem.



		Rhodium (Chief Bee) 07-29-03 01:19 No 450491				Full procedure patented
						The whole procedure from cocaine to the 4-Fluorophenyltropane (including the preparation of the 4-Fluorophenylmagnesium bromide from p-Fluorobromobenzene) can be read on page 14 of Patent EP604354 - but the language is extremely technical.



		SilverSurfer (Hive Bee) 07-29-03 19:40 No 450592				GrignardQuest
						Is that a kind of 1,4 Addition? The only purpose of your life may be to serve as a warning to others http://www.despair.com



		Rhodium (Chief Bee) 07-29-03 21:43 No 450606				Yes, and I know that the details are discussed
						Yes, and I know that the details are discussed in another thread on this topic.

All 11 posts	End of thread	Top