Carroll F I, Abraham P, Parham K, Bai X, Zhang X, Brine G A, Mascarella S W, Martin B R, May E L, Sauss C
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709.
J Med Chem. 1992 Jul 24;35(15):2812-8. doi: 10.1021/jm00093a014.
The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.
N-烯丙基-N-去甲美沙酮（2；SKF 10047，NANM）的光学对映体是最初用于将σ受体与其他受体（如PCP（NMDA）、阿片类和多巴胺受体）区分开来进行分类的化合物。后来的研究表明，（+）-N-（二甲基烯丙基）-N-去甲美沙酮[（+）-4，（+）-喷他佐辛]对σ受体更具效力和选择性。为了获得更多的构效关系信息，制备了几种N-取代的N-去甲美沙酮类似物，并评估了它们对σ-1（[3H]-（+）-3-PPP或[3H]-（+）-喷他佐辛）、PCP（[3H]TCP）和μ阿片（[3H]DAMGO）受体的结合亲和力。（+）-N-苄基-N-去甲美沙酮[（+）-10]对σ位点具有亚纳摩尔亲和力，Ki = 0.67。类似物（+）-10相对于PCP和μ阿片受体对σ受体的选择性分别大于14000倍和2400倍。N-取代的N-去甲美沙酮对σ位点具有对映选择性。（+）-N-苄基类似物（+）-10相对于（-）-10显示出55倍的选择性。数据分析还表明，（+）-去甲美沙酮[（+）-1][Ki = 30 nM]对PCP受体具有最高亲和力。然而，（+）-美沙酮[（+）-5]（Ki = 41 nM）是相对于σ（51倍）和μ阿片（大于200倍）位点对PCP受体最具选择性的化合物。
