Chen Y L, Wang T C, Chang N C, Chang Y L, Teng C M, Tzeng C C
School of Chemistry, Kaohsiung Medical College, Taiwan, R.O.C.
Chem Pharm Bull (Tokyo). 1998 Jun;46(6):962-5. doi: 10.1248/cpb.46.962.
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.
合成了香豆素、萘和喹啉的某些α-亚甲基-γ-丁内酯衍生物，并评估了它们对离体大鼠胸主动脉的血管舒张作用。内酯C2位带有脂肪族甲基取代基的7-[(2,3,4,5-四氢-2-甲基-4-亚甲基-5-氧代-2-呋喃基)甲氧基]-2H-1-苯并吡喃-2-酮，在对抗高钾(80 mM)培养基、钙离子(1.9 mM)诱导的血管收缩以及去甲肾上腺素(NE, 3 μM)诱导的相性和强直性收缩方面，比其C2位为苯基的类似物更具活性(2a对2b；2c对2d；2e对2f；2g对2h)。尽管3-氯-7-[(2,3,4,5-四氢-2-甲基-4-亚甲基-5-氧代-2-呋喃基)甲氧基]-4-甲基-2H-1-苯并吡喃-2-酮(2g)在低至10微克/毫升的浓度下对NE诱导的相性和强直性收缩表现出最有效的抑制活性，但它对NE受体既有亲和力又有引发血管收缩的内在活性。然而，8-[(2,3,4,5-四氢-2-甲基-4-亚甲基-5-氧代-2-呋喃基)甲氧基]喹啉(10a)和其他喹啉衍生物(11a、12a)是NE受体的纯不可逆非竞争性阻滞剂，没有内在活性。芳环在α-亚甲基-γ-丁内酯的血管舒张作用中起重要作用；萘无活性，喹啉仅对α受体有亲和力，而香豆素既有亲和力又有内在活性。
