title: Binding of tetrahydrocarboline derivatives at human 5-HT5A receptors.
abstract: On the basis of an earlier finding that 5-methyl-5H-1,2,3,4-tetrahydropyrido[4,3-b]indole (5-methyl-1,2,3,4-tetrahydro-gamma-carboline; 1) binds at murine 5-HT(5A) receptors, preliminary structure-affinity studies were conducted. The present investigation extends these structure-affinity studies using human 5-HT(5A) receptors and examined additional analogues of 1. It was found (a) that there is little interspecies difference for the affinities of these compounds, (b) that an intact 1,2,3,4-tetrahydro-gamma-carboline ring system seems optimal and an N(2)-(3-(substituted-phenoxy)propyl) moiety results in high affinity, (c) that structurally related 1,2,3,4-tetrahydro-beta-carbolines also bind at 5-HT(5A) receptors, and (d) that all examined derivatives also possess affinity for 5-HT(2A) receptors. Evidence is provided that 5-HT(5A) and 5-HT(2A) receptor affinities probably do not covary and that it might be possible, with continued investigation, to develop analogues with enhanced 5-HT(5A) selectivity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: Nantaka
authors.initials: N
authors.lastname: Khorana
authors.forename: Carol
authors.initials: C
authors.lastname: Smith
authors.forename: Kathy
authors.initials: K
authors.lastname: Herrick-Davis
authors.forename: Anil
authors.initials: A
authors.lastname: Purohit
authors.forename: Milt
authors.initials: M
authors.lastname: Teitler
authors.forename: Brian
authors.initials: B
authors.lastname: Grella
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor