Selective pharmacophore design for α1-adrenoceptor subtypes

α1-Adrenoceptors are G-protein coupled receptors found in a variety of vascular tissues and responsible for vasoconstriction. Selectivity for each of the three subtypes is an important consideration in drug design in order to minimise the possibility of side effects. Using Catalyst® we developed ligand-based pharmacophores from α1a,b,d-selective antagonists available in the literature using three separate training sets. Four-feature pharmacophores were developed for the α1a and α1b subtype-selective antagonists and a five-feature pharmacophore was developed for the α1d subtype-selective antagonists. The α1a pharmacophore represents both class I and II compounds with good predictivity for other compounds outside the training set as well. The α1b pharmacophore best predicts the activity of prazosin analogues as these make up the majority of α1b-selective antagonists. Unexpectedly, no positive ionisable feature was incorporated in the α1b pharmacophore. The α1d pharmacophore was based primarily on one structural class of compounds, but has good predictivity for a heterogeneous test set. Preliminary docking studies using AutoDock and optimised α1-adrenoceptor homology models, conducted with the antagonists prazosin (32) and 66, showed good agreement with the findings from the pharmacophores.