(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6]-naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity

J Med Chem. 1995 Jan 6;38(1):28-33. doi: 10.1021/jm00001a007.

Abstract

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]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-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 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 pKB value of 7.34.

MeSH terms

  • Animals
  • Kinetics
  • Male
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / pharmacology*
  • Rats
  • Rats, Inbred WKY
  • Rats, Sprague-Dawley
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology*

Substances

  • Naphthyridines
  • Serotonin Antagonists
  • octahydro-7H-10-methylindolo(1,7-bc)(2,6)-naphthyridine