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In this study four and five-feature pharmacophores for selective antagonists at each of the three α 1 -adrenoceptor (AR) subtypes were used to identify novel α 1 -AR subtype selective compounds in the National Cancer Institute and Tripos LeadQuest databases. 12 compounds were selected, based on diversity of structure, predicted high affinity and selectivity at the α 1D - subtype compared to α 1A - and α 1B -ARs. 9 out of 12 of the tested compounds displayed affinity at the α 1A  and α 1D  -AR subtypes and 6 displayed affinity at all three α 1 -AR subtypes, no α 1B -AR selective compounds were identified. 8 of the 9 compounds with α 1 -AR affinity were antagonists and one compound displayed partial agonist characteristics. This virtual screening has successfully identified an α 1A/D -AR selective antagonist, with low µM affinity with a novel structural scaffold of a an isoquinoline fused three-ring system and good lead-like qualities ideal for further drug development.

A Novel Structural Framework for α1A/D-Adrenoceptor Selective Antagonists Identified Using Subtype Selective Pharmacophores