Resolved N,N-dialkylated 2-amino-8-hydroxytetralins: stereoselective interactions with 5-HT1A receptors in the brain

The enantiomers of the N,N-dimethylamino (1), N,N-diethylamino (2), and N,N-dibutylamino (4) derivatives of 8-hydroxy-2-(dipropylamino)tetralin (8-OH DPAT; 3) have been synthesized. The compounds have been tested for activity at central 5-hydroxytryptamine and dopamine receptors by use of biochemical and behavioral tests in rats. In addition, the ability of the enantiomers of 1-4 to displace [3H]-8-OH DPAT from 5-HT1A binding sites was evaluated. Rank order of potencies in the in vivo tests corresponded to that observed in the 5-HT1A binding assay. In all three tests, the enantiomeric potency ratio was about 10 for 1 and 2 and only around 2-4 for 3 and 4. The more potent enantiomer of 1-3 had the R configuration. In contrast, (S)-4 seemed to be slightly more potent than (R)-4.