.ALPHA.-Methylene-.GAMMA.-butyrolactones: Synthesis and Vasorelaxing Activity Assay of Coumarin, Naphthalene, and Quinoline Derivatives.

Certain alpha-methylene-gamma-butyrolactone derivatives of coumarin, naphthalene, and quinoline were synthesized and evaluated for vasorelaxing effects on isolated rat thoracic aorta. The 7-[(2,3,4,5-tetrahydro-2-methyl-4-methylene-5-oxo-2-furanyl)methoxy]-2H- 1- benzopyran-2-ones, which have an aliphatic methyl substituent at the lactone C2, were more active than their C2-phenyl counterparts against high-K+ (80 mM) medium, Ca2+ (1.9 mM)-induced vasoconstriction and the norepinephrine (NE, 3 microM)-induced phasic and tonic constrictions (2a vs. 2b; 2c vs. 2d; 2e vs. 2f; 2g vs. 2h). Although 3-chloro-7-[(2,3,4,5-tetrahydro-2-methyl-4-methylene-5-oxo-2- furanyl)methoxy]-4-methyl-2H-1-benzopyran-2-one (2g) demonstrated the most potent inhibitory activities on the NE-induced phasic and tonic constrictions at concentrations of as low as 10 micrograms/ml, it possesses both affinity for NE-receptor and intrinsic activity to trigger the vasoconstriction. However, 8-[(2,3,4,5-tetrahydro-2-methyl-4-methylene-5-oxo-2- furanyl)methoxy]quinoline (10a) and other quinoline derivatives (11a, 12a) are pure irreversible non-competitive blockers of NE-receptor with no intrinsic activity. The aromatic ring played an important role in the vasorelaxing effects of alpha-methylene-gamma-butyrolactones; naphthalene was inactive, quinolines exhibited only affinity to the alpha-receptor, and coumarins possessed both affinity and intrinsic activity.