Brandt W, Barth A
Department of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Germany.
SAR QSAR Environ Res. 1993;1(4):345-8. doi: 10.1080/10629369308029896.
Using the molecular modeling program SYBYL, a conformational analysis of epibatidine has been performed. Two pairs of stable conformations due to the rotational degree of freedom for the pyridine ring have been found. These conformations were compared with morphine regarding spatial arrangements as well as electronic aspects. A very close agreement between the essential receptor positions occurring in morphine and epibatidine could be demonstrated. The protonable nitrogen atom in epibatidine is in exactly the same spatial position as in morphine, if the pyridine ring and the phenolic ring of morphine were matched to each other. Interestingly, it is also apparent that the pyridine nitrogen atom is in a close position to the bridging oxygen atom of morphine. Furthermore, the chlorine substituent fits very well with the hydroxyl group of morphine. A chemical reaction is postulated to permit epibatidine to function as an analgesic. The carbon-chlorine bond should be activated by the neighbourhood of the nitrogen atom in the pyridine ring and therefore undergo a chemical reaction resulting in formation of a covalent bond, perhaps of an oxygen bridge between the opioid receptor and epibatidine.
利用分子模拟程序SYBYL，对埃博霉素进行了构象分析。由于吡啶环的旋转自由度，发现了两对稳定构象。将这些构象与吗啡在空间排列和电子方面进行了比较。可以证明吗啡和埃博霉素中出现的基本受体位置非常吻合。如果将吗啡的吡啶环和酚环相互匹配，埃博霉素中可质子化的氮原子与吗啡中的空间位置完全相同。有趣的是，吡啶氮原子也明显与吗啡的桥连氧原子位置相近。此外，氯取代基与吗啡的羟基配合得非常好。推测发生一种化学反应使埃博霉素发挥镇痛作用。碳-氯键应被吡啶环中氮原子的邻位激活，因此发生化学反应形成共价键，可能是阿片受体与埃博霉素之间形成氧桥。
