An improved nicotinic pharmacophore and a stereoselective CoMFA-model for nicotinic agonists acting at the central nicotinic acetylcholine receptors labelled by.
A study of a series of compounds with agonistic effect at the alpha4beta2 nicotinic acetylcholine receptors resulted in an improved pharmacophore model as well as a CoMFA model. The pharmacophore was composed of three pharmacophoric elements: (1) a site point (a) corresponding to a protonated nitrogen atom, (2) a site point (b) corresponding to an electronegative atom capable of forming a hydrogen bond, and (3) the centre of a heteroaromatic ring or a C=O bond (c). The pharmacophoric elements were related by the following parameters: (a-b) 7.3-8.0 A, (a-c) 6.5-7.4 A, and the angle between the two distance vectors (delta bac) 30.4-35.8 degrees. In addition to this, a stereoselective CoMFA model was developed, which showed good predictability even for compound classes not present in the training set.
Tønder
J E
JE
Health Care Discovery, Novo Nordisk A/S, Måløv, Denmark.
Olesen
P H
PH
Hansen
J B
JB
Begtrup
M
M
Pettersson
I
I
D000818:Animals; D002217:Carbachol / Q000031:analogs & derivatives / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D017076:Computer-Aided Design; D015195:Drug Design; D066298:In Vitro Techniques; D008956:Models, Chemical; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D014316:Tritium
D018722:Nicotinic Agonists; D011950:Receptors, Cholinergic; D014316:Tritium; C053765:N-methylcarbamylcholine; D002217:Carbachol