PHARMACOPHORE DEVELOPMENT FOR ANTAGONISTS AT ALPHA(1) ADRENERGIC-RECEPTOR SUBTYPES

Many receptors, including a, adrenergic receptors, have a range of sub types. This offers possibilities for the development of highly selecti ve 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 molec ular design process, structural features necessary for the selective a ffinity for alpha(1A) and alpha(1B) adrenergic receptors have been inv estigated. The molecular modelling software (particularly the Apex mod ule) of Molecular Simulations, Inc. was used to develop pharmacophore models for these two subtypes. Low-energy conformations of a set of kn own 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 i n the training set. The critical structural feature for selectivity be tween the alpha(1A) and alpha(1B) adrenergic receptor sites is the dis tance between the basic nitrogen atom and the centre of an aromatic ri ng system. This will be exploited in the design and synthesis of struc turally new selective antagonists for these sites.