title: Structural determinants of 5-HT1A versus 5-HT1D receptor binding site selectivity.
abstract: A structure-activity analysis was used to identify selective 5-HT1A versus 5-HT1D receptor agents. An analysis of published data identified 13 drugs which display nanomolar affinity for the 5-HT1A receptor and that have been analyzed at 5-HT1D receptor binding sites. Four agents display greater than or equal to 100-fold selectivity for the 5-HT1A receptor. Two structural features were identified which hypothetically result in selectivity for 5-HT1A versus 5-HT1D binding sites. The linkage of an indole ring to a basic nitrogen atom via the 4 position on the indole ring or the absence of an indole ring are two features which lower the affinity for the 5-HT1D receptor, but do not necessarily lower the affinity for the 5-HT1A receptor. A series of 7 agents (5 indoles, 2 quinolines) was identified which met these hypothetical selectivity criteria. These compounds were then analyzed in radioligand binding studies. These 7 agents display affinities of 1.3-170 nM for the 5-HT1A receptor binding site, and 1,800-13,000 nM for the 5-HT1D receptor binding site. All 7 agents display greater than or equal to 47-fold selectivity for the 5-HT1A versus 5-HT1D site and 4 of the agents are greater than 100-fold selective. Compound No. 1 (N,N'-bis[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-meth ane) and compound No. 2 (N8-[3-(4-indolyloxy)-2-hydroxypropyl]-N1-(propioloyl)-(Z)-1 ,8-diamino-p-methane) are the most selective agents yet described for 5-HT1A versus 5-HT1D receptor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Neurology, Stanford University School of Medicine, CA 94305.
authors.forename: M A
authors.initials: MA
authors.lastname: Harrington
authors.forename: A J
authors.initials: AJ
authors.lastname: Sleight
authors.forename: J
authors.initials: J
authors.lastname: Pitha
authors.forename: S J
authors.initials: SJ
authors.lastname: Peroutka
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D004146:Dioxanes; D004873:Ergolines; D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D005576:Colforsin; D012701:Serotonin; D000262:Adenylyl Cyclases