An improved nicotinic pharmacophore and a stereoselective CoMFA-model for nicotinic agonists acting at the central nicotinic acetylcholine receptors labelled by [H-3]-N-methylcarbamylcholine

A study of a series of compounds with agonistic effect at the alpha4 beta2 nicotinic acetylcholine receptors resulted in an improved pharmacophore mod el as well as a CoMFA model. The pharmacophore was composed of three pharma cophoric elements: (1) a site point (a) corresponding to a protonated nitro gen atom, (2) a site point (b) corresponding to an electronegative atom cap able of forming a hydrogen bond, and (3) the centre of a heteroaromatic rin g or a C=O bond (c). The pharmacophoric elements were related by the follow ing parameters: (a-b) 7.3-8.0 Angstrom, (a-c) 6.5-7.4 Angstrom, and the ang le between the two distance vectors (Delta bac) 30.4-35.8 degrees. In addit ion to this, a stereoselective CoMFA model was developed, which showed good predictability even for compound classes not present in the training set.