title: Development of a receptor-interaction model for serotonin 5-HT2 receptor antagonists. Predicting selectivity with respect to dopamine D2 receptors.
abstract: A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-,1-(4- piperidinyl)-,3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyprohepatadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D2 receptor antagonists suggests a common pharmacophore for dopamine D2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.
authors.affiliation: H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Andersen
authors.forename: T
authors.initials: T
authors.lastname: Liljefors
authors.forename: K
authors.initials: K
authors.lastname: Gundertofte
authors.forename: J
authors.initials: J
authors.lastname: Perregaard
authors.forename: K P
authors.initials: KP
authors.lastname: Bøgesø
mesh_terms: D007189:Indans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship
chemical_list: D007189:Indans; D007211:Indoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists