J. Nozulak et al., YDRO-7H-10-METHYLINDOLO[1,7-BC][2,6]-NAPHTHYRIDINE - A 5-HT(2C())2B) RECEPTOR ANTAGONIST WITH LOW 5-HT(2A) RECEPTOR AFFINITY/, Journal of medicinal chemistry, 38(1), 1995, pp. 28-33
The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-H
T2A receptor antagonist. The compound was synthesized in seven steps s
tarting from indoline and isonicotinic acid chloride. The key step is
a photocyclization of the indolinyl tetrahydropyridinocarbamic acid et
hyl ester 4 to the s-octahydroindolo[1,7-bc][2,6]naphthyrdinecarbamic
acid ethyl ester 5. The synthesis was accomplished by reduction with a
luminum hydride and racemic resolution. The indolonaphthyridine 8 exer
ted 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 i
nositol phosphates in pig choroid plexus cells (pK(B) 7.13). Compound
8 dose-dependently inhibited the ACTH response to MK-212 in rats and t
he 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.