• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Drug designs. (MedicinalUser SAR thread)

Smyth2 said:
I appreciate that 4-Methylthioamphetamine, Aleph, & McN5652 are special cases but these are all para-substituted.
Click to expand...

McN5652 and JNJ-7925476 both appear to somewhat SERT selective.

But I noted that one ligand supplier was offering para ethynyl amphetamine AS a SERT ligand. Now given the affinity, do we know the ED50 of those two compounds? Because even if it turns out that the para thiomethoxy moiety IS an MAOI, if the ED50 is very low, that likely would not be a risk.

That's why I suggested that the BEST repacement for 4MMC was probably 4YNC (4-ethynyl methcathinone) as that ethynyl moiety IS labile. Hydration simply leads to an acetopenone which itself can be further oxidized to the ketol thence the α-keto carboxylic acid. All three metabolites readily being conjugaged and excreted.

SURELY it has to be a safer option than things like 4BMC and 4CMC? Halogens are far less labile. Yes, dehalogenation can occur, but that's CYP2E1 rather than both CYP2E1 AND CYP3A4, not to mention the rearrangement to said acetophenone is also an ATP substrate as well as CYP1A2 rearrangement to the coresponding phenylacetate. It just seems safer to me.

I'm not expert but surely if a consumer ends up suffering the chronic toxicity of those para halogen cathinones, likely they will likely not reorder.
 
Smyth2 said:
If you want a dopaminergic stimulant check out the wikipedia page on PR-000608 and the related background work.

I can see that you are trying to invent new compounds related to modafinil but really there is no need since there is JJC8-088 already.
Click to expand...

The former is in that 'big book of stimulants' acaemic paper by an Indian (?) researcher. You know the one I mean - it covers every (then) known class of stimulant.

The latter IS new to me.

I recall a potent tricyclic (I mean just three rings, not 'tricyclic' as it applies to antidepressants) which was used as a diet medication with 1-4mg taken once a day. That paper mentioned that expanding the 5-membered ring to a 6-membered ring increased activity by an order of magnitude. Not a facile target BUT it's always good to have another scaffold if one intends to build a training set. It had a para chloro on the aromatic although the patent covered many such ring-substitutions... but not the para methoxy, para thiomethoxy or para ethynyl as none of those has been identified as key moieties for altering the NET:DAT:SERT ratio.

In that case it was the complex synthesis and unfavourable pharmokinietics that meant it wasn't abused (AFAIK). Two hours before you feel it, then it works for 14-16 hours. If one could alrer those pharokintetics.... maybe you have something interesting, especially if it follows the same ring-substitution patterns as dichlofensine and those two mad ones that McN and JNJ patented. A selective SERT modulator that is non-toxic might prove to be a reasonable antidepressant?

The name will come to me at some point.
 
Last edited:
One that has struck my mind is a triglyceride of GHB (so 3 GHB molecules with their carboxyl groups esterified to each alcohol on a glycerol (1,2,3-propane-triol molecule). Gotta get dinner cooking or I’d draw it out.
 
Skorpio said:
One that has struck my mind is a triglyceride of GHB (so 3 GHB molecules with their carboxyl groups esterified to each alcohol on a glycerol (1,2,3-propane-triol molecule). Gotta get dinner cooking or I’d draw it out.
Click to expand...
I'm always looking foreword to seeing your Designs. :)
 

THIS paper is the one I referrd to.

Mazindol was the name of the medication I singularly failed to remember the name of. The keto tautomer mentioned in the paper may well overlay setazindol.

Homomazindol is the specific sacaffold I was trying to flag does appear to be more active. That wouuld support the hypothesis of the two overlaying as the basic N would then overlay the basic N of sentazindol more closely.

sentazionol patent - US-5162371-A
mazindol patent - US-3905994-A
 
Last edited:
Benocyclidine, (R)-ketamine and their homologues & the pyrrolidinophenones, their homologues and bioisosteres are not covered although it does appear that they all demonstrate activities common to cocaine.

Amfonelic acid is an odd one. I only know people have compared it's activity to cocaine. On a transport and binding site(s) basis, I don't know if ANY of the compounds I have listed were omitted because they did not act on the same site(s), if their action wasn't understood at the time and/or for other reasons.

N-[1-(2-Benzo[b]Thiophenyl)Cyclohexyl]- Piperidine (BTCP) Exerts Cocaine-Like Actions on Drug-Maintained Responding in Rats | 10.1016/s0893-133x(00)00104-4_Science Hub

www.tesble.com www.tesble.com

Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose | 10.3389/fnins.2015.00324_Science Hub

www.tesble.com www.tesble.com

Pharmacologic properties and mechanism of action of amfonelic acid | 10.1016/0014-2999(70)90206-2_Science Hub

www.tesble.com www.tesble.com

I've only provided links to one paper covering each of the classes mentioned but there are plenty of them out there if one looks.
 
You must log in or register to reply here.
Top