(+)-cis-4,5,7a,8,9,10,11,11a-Octahydro-7H-10-methylindolonaphthyridine: A 5-HT2C/2B Receptor Antagonist with Low 5-HT2A Receptor Affinity

Article abstract of DOI:10.1021/jm00001a007

The indolonaphthyridine 8 is described as a selective 5-HT_2C/2B vs 5-HT_2A receptor antagonist.The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride.The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis-octahydroindolo<1,7-bc><2,6>naphthyridinecarbamic acid ethyl ester 5.The synthesis was accomplished by reduction with aluminum hydride and racemic resolution.The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT_2C receptor ligand (pK_D 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pK_B 7.13).Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc.Compound 8 acted as a 5-HT_2B receptor antagonist at the rat stomach fundus with a pK_B value of 7.34.