title: Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives.
abstract: The conformationally restricted linear tricyclic analogs of 5- and 8-hydroxy-2-(di-n-propylamino)-tetralins were investigated for their serotonergic and dopaminergic properties. These cis and trans analogs of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (3), where a five-membered ring is fused between the nitrogen and C-3 carbon of 2-aminotetralin, were synthesized from 5-methoxy- and 8-methoxytetralones. The enantiomers of trans-5-methoxy-N-n-propyl and -N-allyl analogs were obtained via fractional recrystallization of their di-p-toluoyl-L (or D) tartaric acid salts. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. In the 5-substituted series (R1 in 3), the trans isomers were found to possess higher levels of pharmacological activity then the corresponding cis isomers. The trans-5-methoxy analogs showed selective 5-HT1A receptor activity in vitro but displayed mixed 5-HT1A and D2 agonist properties in vivo. The corresponding trans-5-hydroxy analogs were found to be potent D2 agonists with full intrinsic activity. An examination of nitrogen substitution (R2 in 3) revealed that analogs with either an allyl or an n-propyl group displayed equipotent activities. Substitution with a cyclopropylmethyl or benzyl group resulted in reduced activity. Among the resolved analogs tested, the activity was found to reside exclusively in the (3aS)-(-)-enantiomers. In the 8-substituted series (R1 in 3), only 8-methoxy-N-allyl analogs were synthesized and evaluated. In this case, both cis and trans isomers showed equally weak in vitro 5-HT1A receptor agonist activity devoid of dopaminergic effects. The presence of an additional methyl group at the C-2 position (R3 in 3) of the cis-(+/-)-8-methoxy-N-n-propyl analog resulted in enhancement of in vitro 5-HT1A receptor binding affinity, with the (2 beta,3a alpha,9a alpha)-(+/-)-isomer displaying potency 35 times greater than the (2 alpha,3a alpha,9a alpha)-(+/-)-isomer.
authors.affiliation: Medicinal Chemistry Research, 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 A
authors.initials: RA
authors.lastname: Lahti
authors.forename: R B
authors.initials: RB
authors.lastname: McCall
authors.forename: M F
authors.initials: MF
authors.lastname: Piercey
authors.forename: P J
authors.initials: PJ
authors.lastname: Schreur
authors.forename: P F
authors.initials: PF
authors.lastname: Von Voigtlander
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
authors.forename: C G
authors.initials: CG
authors.lastname: Chidester
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002415:Cats; D002417:Cattle; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; 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; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015259:Dopamine Agents; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes