A novel structural framework for α(1A/D)-adrenoceptor selective antagonists identified using subtype selective pharmacophores.
AuthorStoddart, ES; Senadheera, S; MacDougall, IJA; Griffith, R; Finch, AM
Source TitlePLoS One
PublisherPublic Library of Science (PLoS)
University of Melbourne Author/sSENADHEERA, SEVVANDI
AffiliationSchool of BioSciences
Document TypeJournal Article
CitationsStoddart, E. S., Senadheera, S., MacDougall, I. J. A., Griffith, R. & Finch, A. M. (2011). A novel structural framework for α(1A/D)-adrenoceptor selective antagonists identified using subtype selective pharmacophores.. PLoS One, 6 (5), pp.e19695-. https://doi.org/10.1371/journal.pone.0019695.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091868
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.
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