Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300

Article abstract of DOI:10.1002/1521-4184(200107)334:7<241::AID-ARDP241>3.0.CO;2-B

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT_2A receptors (rat tail artery) and H₁ receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4, 5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA₂ = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA₂ = 9.55). Compound 19 displayed moderate H₁-antihistaminic activity in the guinea-pig ileum assay (pA₂ = 7.37).