Matching Pharmacophores

[Hammilton]

I had thought that this wasn't actually a fruitful way to go, but after I accidentally came up with the deschloro analogue of Tonquil, I decided it might be worth posting.

I had the idea of 'designing' molecules that would putatively be stimulants based upon their ability to match the pharmacophore of cocaine / dimethocaine in 3D. I placed highest importance on the ability of the amines and the phenyls (or equivalent ring) to match, followed by the carboxyl oxygen and then the rest of the chain linking the phenyl and amine.

I only considered the amines. I have done more extensive comparison with adamantane rings replacing tropane (makes sense, now that I know nitrogen free analogues are active). I also compared Bromantane (sp?) to Cocaine and found that it matched up very well too- the space filling adamantane group filling the same place the tropane group does, and the phenyls closely aligned. Not the best alignment, though. I expanded on that theme quite a bit, and many fit very well. Assuming that the adamantane structure is able to fill the same space tropane does with cocaine.

Here's an image of the structures I've spent the most time thinking over. None look obviously toxic. IIRC,

Here it is:



I don't know that any of these have been tried, I removed Clofenciclan from the drawing because it's obviously known (Unscheduled, though).

Only the three marked here are of any real interest AFAICT.

On Bluelight or Blacklight I have seen someone mention doing this same sort of thing with phenethylamines. The best I've been able to come up with that can't have the AMP skeleton the way all of the cathinones, pyrovalerones, 2-phenylmorpholines. So far the best not-PEA amphetamine analogue is 1-(1-aminocyclohexyl)-2-phenylethanone. It's not bad. It might be worth trying. I suspect it's different enough that any PCP like effects.

Any suggestions on usefulness of this as a method would be useful.

 

[elfspice]

looks very interesting. from this model how does that relate to this:

i need to get a chem modelling program again, iirc the bromine is a big fatass molecule not too far off the size of a benzene molecule in size and not too far off in its charge pattern (obviously lacking the central pole positive region).

 

[Hammilton]

I ran a few of these through PASS. This is some of what "best" gets at <50% (still in order)

27 Substructure descriptors; 0 new.
41 Possible activities at Pa > 50%
Pa Pi for Activity:
0,889 0,007 Psychosexual dysfunction treatment
0,876 0,007 Cardiovascular analeptic
0,814 0,016 CC chemokine 2 receptor antagonist
0,778 0,007 Antiparkinsonian
0,811 0,064 Fibrinogen receptor antagonist
0,759 0,027 Dopamine D4 agonist
0,714 0,006 Peptidoglycan glycosyltransferase inhibitor
0,691 0,005 Dopamine agonist
0,694 0,014 Antidepressant
0,712 0,061 Cardioprotectant
0,681 0,040 Antineurotic
0,704 0,068 Urologic disorders treatment
0,636 0,004 Melatonin 1 antagonist
0,643 0,025 Membrane permeability inhibitor
0,623 0,034 Neurotransmitter uptake inhibitor
0,640 0,051 Antineurotoxic
0,603 0,028 Psychotropic
0,600 0,038 Tocolytic
0,603 0,058 Torsades de pointes
0,564 0,020 Prostaglandin H2 antagonist
0,561 0,018 Prostaglandin E1 antagonist
0,572 0,042 Dependence treatment
0,532 0,007 5 Hydroxytryptamine 1A agonist
0,622 0,100 2-Haloacid dehalogenase (configuration-inverting) inhibitor
0,596 0,078 CYP2D16 substrate
0,597 0,081 Arrhythmogenic
0,510 0,008 5 Hydroxytryptamine agonist
0,527 0,025 Cyclic AMP agonist
0,528 0,032 Vasodilator, renal
0,540 0,047 Calmodulin antagonist
0,508 0,019 Analeptic
0,538 0,058 Antidiarrheal
0,507 0,032 Anxiolytic
0,502 0,032 Corticotropin releasing factor antagonist
0,503 0,033 Sigma receptor agonist

Bromantane generates the following

25 Substructure descriptors; 0 new.
13 Possible activities at Pa > 50%
Pa Pi for Activity:
0,887 0,032 Prolyl aminopeptidase inhibitor
0,709 0,007 Antiviral (Influenza)
0,650 0,010 Immunostimulant
0,652 0,013 Cell adhesion molecule inhibitor
0,645 0,025 Antihypoxic
0,591 0,016 CDK2/cyclin A inhibitor
0,594 0,058 Antineoplastic (brain cancer)
0,589 0,068 Antineoplastic (colorectal cancer)
0,549 0,037 Acute neurologic disorders treatment
0,539 0,050 1-Alkyl-2-acetylglycerophosphocholine esterase inhibitor
0,558 0,068 Nootropic
0,510 0,121 Cardiotoxic
0,512 0,142 Arrhythmogenic


Bromantane fits in best with cocaine. Compare it to cocaine in 3D. The adamantane ring(s?) probably fits the same slot that the tropane ring does in cocaine. Other than that, the phenyl matches.