Lin C H, Haadsma-Svensson S R, Lahti R A, McCall R B, Piercey M F, Schreur P J, Von Voigtlander P F, Smith M W, Chidester C G
Medicinal Chemistry Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
J Med Chem. 1993 Apr 16;36(8):1053-68. doi: 10.1021/jm00060a014.
The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. 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. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.
