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PLoS One ; 6(5): e19695, 2011 May 10.
Article in English | MEDLINE | ID: mdl-21572949

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.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/chemistry , Receptors, Adrenergic, alpha-1/classification , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Animals , COS Cells , Chlorocebus aethiops , Cloning, Molecular , Databases as Topic , Inositol Phosphates/metabolism , Models, Molecular , Norepinephrine/pharmacology
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