title: A novel structural framework for α(1A/D)-adrenoceptor selective antagonists identified using subtype selective pharmacophores.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Stoddart
authors.forename: Sevvandi
authors.initials: S
authors.lastname: Senadheera
authors.forename: Iain J A
authors.initials: IJ
authors.lastname: MacDougall
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.forename: Angela M
authors.initials: AM
authors.lastname: Finch
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D019992:Databases as Topic; D007295:Inositol Phosphates / Q000378:metabolism; D008958:Models, Molecular; D009638:Norepinephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification* / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D007295:Inositol Phosphates; D018340:Receptors, Adrenergic, alpha-1; D009638:Norepinephrine