(+)-CIS-4,5,7A,8,9,10,11,11A-OCTAHYDRO-7H-10-METHYLINDOLO[1,7-BC][2,6]-NAPHTHYRIDINE - A 5-HT(2C/2B) RECEPTOR ANTAGONIST WITH LOW 5-HT(2A) RECEPTOR AFFINITY

The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A 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]naphthyrdinecarbamic 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-HT2C 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-HT2B receptor antagonist at the rat stomach fundus with a pK(B) value of 7.34.