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Ligand design for alpha(1) adrenoceptor subtype selective antagonists
journal contribution
posted on 2023-05-16, 12:20 authored by Bremner, JB, Coban, B, Griffith, R, Karina GroenewoudKarina Groenewoud, Brian YatesBrian Yatesα1 Adrenoceptors have three subtypes and drugs interacting selectively with these subtypes could be useful in the treatment of a variety of diseases. In order to gain an insight into the structural principles governing subtype selectivity, ligand based drug design (pharmacophore development) methods have been used to design a novel 1,2,3-thiadiazole ring D analogue of the aporphine system. Synthesis and testing of this compound as a ligand on cloned and expressed human α1 adrenoceptors is described. Low binding affinity was found, possibly due to an unfavourable electrostatic potential distribution. Pharmacophore models for antagonists at the three adrenoceptor sites (α(1A), α(1B), α(1D)) were generated from a number of different training sets and their value for the design of new selective antagonists discussed. The first preliminary antagonist pharmacophore model for the α(1D) adrenoceptor subtype is also reported. (C) 2000 Elsevier Science Ltd.
History
Publication title
Bioorganic & Medicinal ChemistryVolume
8Pagination
201-214ISSN
0968-0896Department/School
School of Natural SciencesPublisher
Pergamon-ElsevierPlace of publication
Oxford, UKRepository Status
- Restricted