Williams P S, Sewell R D, Smith H J, Gonzalez J P
Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
J Enzyme Inhib. 1989;3(2):91-101. doi: 10.3109/14756368909030368.
Several penicillins have been found to have pro-antinociceptive properties and also to be enkephalinase (neutral endopeptidase-24.11) inhibitors, carfecillin being the most potent. Carfecillin i.c.v. (but not i.p.) had significant antinociceptive activity in the mouse tail immersion test and completely suppressed abdominal constrictions (acetic acid) in mice (IC50 = 23 micrograms/animal). In combination with (D-Ala2-D-leu5)-enkephalin (DADL) i.c.v. in the abdominal constriction test the complete protection observed was reversed by the opioid receptor antagonist naltrexone. Carfecillin was a competitive inhibitor of enkephalinase from mouse brain striata (IC50 = 207 + 57 nM, cf thiorphan 10.6 +/- 1.9 nM) but did not inhibit other known enkephalin- degrading enzymes. Carfecillin provides a new lead structure for the development of more potent enkephalinase inhibitors.
已发现多种青霉素具有促抗伤害感受特性，并且还是脑啡肽酶（中性内肽酶 - 24.11）抑制剂，卡非西林的活性最强。卡非西林经脑室内（而非腹腔内）给药在小鼠尾部浸没法试验中具有显著的抗伤害感受活性，并且能完全抑制小鼠的腹部收缩（乙酸诱发）（半数抑制浓度 = 23微克/只动物）。在腹部收缩试验中，与脑室内注射的（D - Ala2 - D - leu5）- 脑啡肽（DADL）联合使用时，观察到的完全保护作用被阿片受体拮抗剂纳曲酮逆转。卡非西林是小鼠脑纹状体脑啡肽酶的竞争性抑制剂（半数抑制浓度 = 207 ± 57纳摩尔，对比硫代吗啡酮为10.6 ± 1.9纳摩尔），但不抑制其他已知的脑啡肽降解酶。卡非西林为开发更有效的脑啡肽酶抑制剂提供了一种新的先导结构。
