title: Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.
abstract: The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary. The cis racemate (+/-)-3a, was found to be a selective and potent 5-HT1A receptor agonist with the activity residing in the cis-(3aR)-enantiomer, (-)-3a. The cis-(3aS)-enantiomer (+)-3a and trans-(3aR)-enantiomer (-)-3b displayed partial 5-HT1A agonist activity whereas the other trans-(3aS)-enantiomer (+)-3b showed no activity. The enantiomer (-)-3a was found to be selective in both in vitro and in vivo biochemical/behavioral assays. This compound potently reduced rectal temperature in mice, decreased the firing rate of rat midbrain serotonergic neurons, and suppressed rat brain 5-HT synthesis. This compound also reduced sympathetic nerve discharge and blood pressure in the anesthetized cat and showed activity in the forced swim assay in mice. It exhibited good oral activity in behavioral and biochemical assays and, in fact, had a 46% oral availability in the rat when comparing blood levels of parent drug after iv and po administration. This compound has demonstrated a potential for anxiolytic and antidepressant activity and is currently undergoing clinical evaluation.
authors.affiliation: Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: C H
authors.initials: CH
authors.lastname: Lin
authors.forename: S R
authors.initials: SR
authors.lastname: Haadsma-Svensson
authors.forename: G
authors.initials: G
authors.lastname: Phillips
authors.forename: R B
authors.initials: RB
authors.lastname: McCall
authors.forename: M F
authors.initials: MF
authors.lastname: Piercey
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Svensson
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: C G
authors.initials: CG
authors.lastname: Chidester
authors.forename: P F
authors.initials: PF
authors.lastname: Von Voigtlander
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002415:Cats; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D017366:Serotonin Receptor Agonists; C082409:U 93385