Ligand design for alpha(1) adrenoceptor subtype selective antagonists

alpha(1) Adrenoceptors have three subtypes and drugs interacting selectivel y with these subtypes could be useful in the treatment of a variety of dise ases. In order to gain an insight into the structural principles governing subtype selectivity, ligand based drug design (pharmacophore development) m ethods have been used to design a novel 1,2,3-thiadiazole ring D analogue o f the aporphine system. Synthesis and testing of this compound as a ligand on cloned and expressed human alpha(1) adrenoceptors is described. Low bind ing affinity was found, possibly due to an unfavourable electrostatic poten tial distribution. Pharmacophore models for antagonists at the three adreno ceptor sites (alpha(1A), alpha(1B,) alpha(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 mode l for the alpha(1D) adrenoceptor subtype is also reported. (C) 2000 Elsevie r Science Ltd. All rights reserved.