Author Topic: Cocaine analog not found in TFSE  (Read 2177 times)

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Jubrail

  • Guest
Cocaine analog not found in TFSE
« on: July 23, 2003, 08:29:00 PM »
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.


Rhodium

  • Guest
SAR of piperidine-based cocaine analogs
« Reply #1 on: July 24, 2003, 07:05:00 AM »
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.thevespiary.org/rhodium/Rhodium/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 (missing)

(Rhodium: "Precious metals & Crack", General Discourse)
and the full ref is found in the doc linked in

Post 357128 (missing)

(Rhodium: "Arecocaine", Novel Discourse)
.

Other Cocaine Analogs:

Post 444618 (missing)

(Rhodium: "Dopamine Transporter SAR of Tropanes", General Discourse)

Post 440396 (missing)

(Rhodium: "Novel Sigma-1/DAT ligands", General Discourse)

pericles

  • Guest
analogue's effects
« Reply #2 on: July 24, 2003, 04:48:00 PM »
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 (missing)

(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

  • Guest
cocaine analog synthesis attempt
« Reply #3 on: July 24, 2003, 06:37:00 PM »
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

  • Guest
Whew
« Reply #4 on: July 24, 2003, 11:48:00 PM »
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?


Rhodium

  • Guest
Cocaine to WIN 35,428
« Reply #5 on: July 28, 2003, 12:53:00 AM »
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.thevespiary.org/rhodium/Rhodium/pdf/anhydroecgonine.2-tropinone.pdf)
DOI:

10.1021/jo9710083



Then you use that, together with the procedure from the article in

Post 221796 (missing)

(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 (missing)

(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 (missing)

(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.thevespiary.org/rhodium/Rhodium/pdf/cocaineanalogs.pdf


Jubrail

  • Guest
OK
« Reply #6 on: July 28, 2003, 12:58:00 AM »
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.


pericles

  • Guest
4-fluorophenylmagnesium bromide
« Reply #7 on: July 29, 2003, 12:34:00 AM »
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

  • Guest
Full procedure patented
« Reply #8 on: July 29, 2003, 03:19:00 AM »
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

  • Guest
GrignardQuest
« Reply #9 on: July 29, 2003, 09:40:00 PM »
Is that a kind of 1,4 Addition?


Rhodium

  • Guest
Yes, and I know that the details are discussed
« Reply #10 on: July 29, 2003, 11:43:00 PM »
Yes, and I know that the details are discussed in another thread on this topic.