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

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Abstract

A study of a series of compounds with agonistic effect at the α4β2 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 Å, (a–c) 6.5–7.4 Å, and the angle between the two distance vectors (Δbac) 30.4–35.8°. In addition to this, a stereoselective CoMFA model was developed, which showed good predictability even for compound classes not present in the training set.

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Authors and Affiliations

  1. Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark

    Janne E. Tønder, Preben H. Olesen, John Bondo Hansen & Ingrid Pettersson

  2. Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Mikael Begtrup

Authors
  1. Janne E. Tønder

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  2. Preben H. Olesen

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  3. John Bondo Hansen

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  4. Mikael Begtrup

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  5. Ingrid Pettersson

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Tønder, J.E., Olesen, P.H., Hansen, J.B.et al. An improved nicotinic pharmacophore and a stereoselective CoMFA-model for nicotinic agonists acting at the central nicotinic acetylcholine receptors labelled by [3H]-N-methylcarbamylcholine.J Comput Aided Mol Des15, 247–258 (2001). https://doi.org/10.1023/A:1008140021426

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