A novel structural framework for α1A/D-adrenoceptor selective antagonists identified using subtype selective pharmacophores

In this study four and five-feature pharmacophores for selective antagonists at each of the three α₁-adrenoceptor (AR) subtypes were used to identify novel α₁-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 α₁-AR subtypes, no α_1B-AR selective compounds were identified. 8 of the 9 compounds with α₁-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.