Pharmacology 3D QSAR of Serotonin Transporter Ligands: CoMFA and CoMSIA Studies

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The 3DQSAR of all SERT inhibitors.

 

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1. US 4595688 Certain Hexahydro-6-Arylprylpyrrolo [2,1-A]Isoquinoline
2. US 4837328 Stereoselective reaction for hexahydro-6-arylpyrrolo(2,1-A) isoquinolines

X	Y	V	W	MA (mg/kg)	ptosis (mg/kg)	DA (nM)	NE (nM)	5-HT (nM)
H	H	H	H	0.34 (0.59)	0.07 (0.05)	11.3 (4.4)	0.60 (0.37)	23.5 (12.4)
H	H	OMe	OMe	15.1	3.8	15.0	53.7	1540
H	H	OH	OH	0.87	0.53	43.5	10.5	124
OMe	H	H	H	0.27	0.03	5.2	0.79	1.7
OH	H	H	H	0.40	0.09	5.1	0.74	3.2
H	OMe	H	H	~0.2	0.07	15.8	0.65	7.2
H	OH	H	H	>10	0.11	10.1	0.85	24.6
H	H	H	OMe	no data	no data	2.8	2.2	4.5
OMe	OMe	H	H	2.0	0.13	71.9	3.4	18.1
OH	OH	H	H	0.19	0.11	10.1	0.81	33.1
Cl	H	H	H	0.55	0.34	1.7	0.16	1.5
H	Cl	H	H	~0.1	<0.1	2.5	0.45	7.3
Cl	H	H	Cl	37.4	~4	3.2	3.2	2.9
Cl	Cl	H	H	0.39	0.14	0.99	0.68	1.8
F	H	H	H	~0.2	~0.2	8.4	1.4	8.5
F	H	H	F	>30	0.05	7.7	0.55	4.4
NH2	H	H	H	~0.2	~0.01	0.86	0.20	44
SMe	H	H	H	>30 (no data)	0.30 (no data)	41.2 (23.5)	3.0 (1.8)	0.62 (0.39)
Ethynyl	H	H	H	~0.5	~0.5	2.6	0.94	1.0
diclofensine			10.9	8.8	10.3
WIN-25978			7.2	41.1	879

I don't think it takes a genius to note that the above compounds are all derived from the amphetamine scaffold. Note that the p-SCH3 is selective to SERT (like 4MTA), p-OCH3 similar but less so (like p-methoxy amphetamine), the m-methoxy more serotonin-selective & the p-Cl is fairly balanced (like p-Cl amphetamine).

What firmly is NOT mentioned is the homologue with the 3,4-methylenedioxy ring or the p-Me, m-OCH3. But given their affinity and LogP, this scaffold might well prove to provide an MDMA-like entactogen with the simple advantage of being at least an order of magnitude more potent. Not easily made, but not controlled.

It's also worth noting that the p,m-dichloro derivative is potent and it makes me wonder what happens to the unwanted enantiomers of sertraline, especially since an earlier antidepressant developed by a Swedish team lacked the 3,4-dichloro and while active, wasn't marketed because it produced euphoria.

If you read the patents to see who THEY reference, you will discover that ALL stimulants are covered thus:

(ring substituted) amphetamines --> (ring substituted) desoxypipradrol (and homologues) --> nomifensine/dichlofensine (and homologues) and the onwards to the scaffold shown above (McN5652/JWJ7925476) and homologues.

I feel it's of value to those seeking to build a training-set. Their are certainly enough scaffolds for one to produce relative spatail positions for the RA (ring aromatics), PI (positively ionizable function) and HBOs (hydrogen-bond acceptors).