Pharmacophore development for antagonists at alpha 1 adrenergic receptor subtypes.

Many receptors, including alpha 1 adrenergic receptors, have a range of subtypes. This offers possibilities for the development of highly selective antagonists with potentially fewer detrimental effects. Antagonists developed for alpha 1A receptors, for example, would have potential in the treatment of benign prostatic hyperplasia. As part of the molecular design process, structural features necessary for the selective affinity for alpha 1A and alpha 1B adrenergic receptors have been investigated. The molecular modelling software (particularly the Apex module) of Molecular Simulations, Inc. was used to develop pharmacophore models for these two subtypes. Low-energy conformations of a set of known antagonists were used as input, together with a classification of the receptor affinity data. The biophores proposed by the program were evaluated and pharmacophores were proposed. The pharmacophore models were validated by testing the fit of known antagonists, not included in the training set. The critical structural feature for selectivity between the alpha 1A and alpha 1B adrenergic receptor sites is the distance between the basic nitrogen atom and the centre of an aromatic ring system. This will be exploited in the design and synthesis of structurally new selective antagonists for these sites.