ALPHA-METHYLENE-GAMMA-BUTYROLACTONES - SYNTHESIS AND VASORELAXING ACTIVITY ASSAY OF COUMARIN, NAPHTHALENE, AND QUINOLINE DERIVATIVES

Certain alpha-methylene-gamma-butyrolactone derivatives of coumarin, n aphthalene, and quinoline were synthesized and evaluated for vasorelax ing effects on isolated rat thoracic aorta. The e-5-oxo-2-furanyl)meth oxy]-2H-1-benzopyran-2-ones, which have an aliphatic methyl substituen t at the lactone C-2, were more active than their C-2-phenyl counterpa rts against high-K+ (80 mM) medium, Ca2+ (1.9 mM)-induced vasoconstric tion and the norepinephrine (NE, 3 mu M)-induced phasic and tonic cons trictions (2a vs. 2b; 2c vs. 2d; 2e vs. 2f; 2g vs, 2h), Although -2-fu ranyl)methoxy]-4-methyl-2H-1-benzopyran-2-one (2g) demonstrated the mo st potent inhibitory activities on the NE-induced phasic and tonic con strictions at concentrations of as low as 10 mu g/ml, it possesses bot h affinity for NE-receptor and intrinsic activity to trigger the vasoc onstriction, However, thyl-4-methylene-5-oxo-2-furanyl)methoxy]quinoli ne (10a) and other quinoline derivatives (11a, 12a) are pure irreversi ble non-competitive blockers of NE-receptor,vith no intrinsic activity , The aromatic ring played an important role in the vasorelaxing effec ts of alpha-methylene-gamma-butyrolactones; naphthalene was inactive, quinolines exhibited only affinity to the alpha-receptor, and coumarin s possessed both affinity and intrinsic activity.