Patel A, Smith H J, Sewell R D
Welsh School of Pharmacy, U.W.C.C., Cardiff U.K.
J Enzyme Inhib. 1991;5(2):133-49. doi: 10.3109/14756369109069066.
4-Carboxymethylamino-4-oxo-3-(4'-aminophenylamino) butanoic acid (25), its ethyl ester (26) and the corresponding unsubstituted-aryl analogues (17) and (16) are fairly potent inhibitors of enkephalinase (neutral endopeptidase; EC 3.4.24.11), Ki = 0.14-0.39 microM, with weak inhibitory potency, Ki = 15-75 microM, towards aminopeptidase MII. In the mouse abdominal constriction test, the esters (26) and (16) showed systemic inhibitory (antinociceptive) activity with ED50 values 62 +/- 3.05 and 81 +/- 1.74 mg/kg respectively. In the mouse tail immersion test, both (26) and (16) exhibited antinociceptive activity when administered intracerebroventricularly and (26) also exhibited a systemic effect which was only partially reversed by naltrexone. The antinociceptive effect seen with (26) reflects its ranking in vitro as an inhibitor of enkephalinase (Ki = 0.14 microM) but it is possible that this effect is not totally opioid-mediated. Compounds (26) and (16) represent the first combined inhibitors of enkephalinase and aminopeptidase MII.
4-羧甲基氨基-4-氧代-3-(4'-氨基苯氨基)丁酸(25)、其乙酯(26)以及相应的未取代芳基类似物(17)和(16)是脑啡肽酶(中性内肽酶；EC 3.4.24.11)的相当有效的抑制剂，抑制常数Ki = 0.14 - 0.39微摩尔，而对氨肽酶MII的抑制效力较弱，抑制常数Ki = 15 - 75微摩尔。在小鼠腹部收缩试验中，酯类化合物(26)和(16)显示出全身抑制(抗伤害感受)活性，半数有效剂量(ED50)值分别为62±3.05和81±1.74毫克/千克。在小鼠甩尾试验中，(26)和(16)经脑室内给药时均表现出抗伤害感受活性，并且(26)还表现出全身效应，而纳曲酮只能部分逆转这种效应。(26)所观察到的抗伤害感受作用反映了其在体外作为脑啡肽酶抑制剂的排名(Ki = 0.14微摩尔)，但这种作用可能并非完全由阿片类物质介导。化合物(26)和(16)代表了首批脑啡肽酶和氨肽酶MII的联合抑制剂。
