CENTRALLY ACTING SEROTONERGIC AND DOPAMINERGIC AGENTS .1. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2,3,3A,4,5,9B-HEXAHYDRO-1H-BENZ[E]INDOLE DERIVATIVES

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5 ,9b-hexahydro-1H-benz[e]-indole derivatives (3) are described. These c ompounds 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 o btained from either fractional recrystallizations of the diastereomeri c salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthe sis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluat ed in the in vitro 5-HT1A and D2 binding assays and selected analogs w ere 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 ana logs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in t he cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nit rogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-me thylbenzyl group resulted in loss of activity. Analogs without aromati c substitution (R1 = H in 3) still showed good 5-HT1A agonist activity , although less potent than the 9-methoxy series. In this case, the tr ans analogs possessed equal or higher in vitro 5-HT1A affinity than th e corresponding cis analogs. Analogs with either 6-methoxy or 6-hydrox y substitution (R1 in 3) were found to display dopamine antagonist pro perties. However, only N-allyl analogs showed this activity. In the 6- methoxy-N-allyl series, the cis analog was found to be more potent tha n the trans analog. Again, between the pair of cis enantiomers, the (3 aR)-(-)-enantiomer showed higher potency. Incorporation of an addition al methyl group into 9-methoxy cis analogs at C-2 resulted in retentio n of potent 5-HT1A agonist activity.