title: Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 2. Effects of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology.
abstract: A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a Ki of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.
authors.affiliation: Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Ennis
authors.forename: P
authors.initials: P
authors.lastname: Stjernlöf
authors.forename: R L
authors.initials: RL
authors.lastname: Hoffman
authors.forename: N B
authors.initials: NB
authors.lastname: Ghazal
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Svensson
authors.forename: H
authors.initials: H
authors.lastname: Wikström
authors.forename: S R
authors.initials: SR
authors.lastname: Haadsma-Svensson
authors.forename: C H
authors.initials: CH
authors.lastname: Lin
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009584:Nitrogen / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011985:Receptors, Serotonin; C082404:8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz(e)indole-1-carbaldehyde; D009584:Nitrogen