ROLE OF SUBSTRATE LIPOPHILICITY ON THE N-DEMETHYLATION AND TYPE-I BINDING OF 3-O-ALKYLMORPHINE ANALOGS
ROLE OF SUBSTRATE LIPOPHILICITY ON THE N-DEMETHYLATION AND TYPE-I BINDING OF 3-O-ALKYLMORPHINE ANALOGS
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DOI：
10.1021/jm00364a002
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发表时间：
1983-01-01
影响因子：
7.3
通讯作者：
HOLTZMAN, JL
中科院分区：
文献类型：
--
作者：
DUQUETTE, PH;ERICKSON, RR;HOLTZMAN, JL
合成了一系列3-O-烷基吗啡类似物[可待因、3-O-乙基-、3-O-丁基-、3-O-丙基-、3-O-戊基-、3-O-己基-、3-O-庚基-、3-O-辛基-、3-O-壬基-、3-O-癸基-和3-O-十二烷基吗啡]，以确定代谢速率、I型结合亲和力和脂溶性之间是否存在良好的相关性。N-去甲基化的Km随着链长从C1增加到C9而下降，而对于链长增加，对于丁基类似物（C4），N-去甲基化的Vmax增加到最大值15.20 nmol/min/（mg蛋白质），然后对于链长大于丁基（C4）的类似物缓慢下降。癸基（C10）和十二烷基（C12）类似物没有显示出活性。亲脂性和Km值之间有很好的相关性，除了可待因和C10和C12类似物。I型结合解离常数（K8）也随着烷基链长度宽度的增加而降低，Ks和log P之间具有良好的相关性。ODmax [最大O-脱烷基化速率]不随类似物链长度的增加而变化。显然，在雄性大鼠肝微粒体中，这一系列化合物的N-脱甲基化催化位点和I型结合位点相似但不同。
A series of 3-O-alkylmorphine analogs [codeine, 3-O-ethyl-, 3-O-butyl-, 3-O-propyl-, 3-O-pentyl-, 3-O-hexyl-, 3-O-heptyl-, 3-O-octyl-, 3-O-nonyl-, 3-O-decyl- and 3-O-dodecylmorphine] was synthesized to determine if there was a good correlation between the rate of metabolism, type I binding affinity and lipid solubility. The Km for the N-demethylation declines with increasing chain length from C1 to C9, while for increasing chain length the Vmax for the N-demethylation increases to a maximum of 15.20 nmol/min per (mg of protein) for the butyl analog (C4) and then slowly declines with analogs with chain lengths greater than butyl (C4). The decyl (C10)and dodecyl (C12) analogs showed no activity. There was a good correlation between the lipophilicity and Km values, except for codeine and the C10 and C12 analogs. The type I binding dissociation constants (K8) also decreased with increasing alkyl chain length width an excellent correlation between the Ks and log P. The ODmax [maximum O-dealkylation rate] did not change with increasing the chain length of the analogs. Apparently, in male rat hepatic microsomes the catalytic site for N-demethylation and the site for type I binding in this series of compounds are similar but distinct.