Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole ring system. 2. Effect of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology

Article abstract of DOI:10.1021/jm00012a022

A series of analogs of the potent and selective 5-HT(1A) agonist 8-(di-n- propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipro-pylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in rive effects, including the establishment of a receptor binding profile for these analogs at the 5-HT(1A), dopamine D-2, dopamine D-3, 5-HT(1Dα), and 5- HT(1Dβ) sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in rive changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT(1A) receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT(1Dα) over the 5-HT(1Dβ) receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT(1A) receptor. Although this compound possessed a K(i) of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP- based intrinsic activity assay.