Glassco W, Suchocki J, George C, Martin B R, May E L
Department of Pharmacology and Toxicology, Medical College of Virginia-Virginia Commonwealth University, Richmond 23298.
J Med Chem. 1993 Oct 29;36(22):3381-5. doi: 10.1021/jm00074a019.
Title compound, 8, has been synthesized from isoquinolinone, 1 (an improved preparation for which is presented) and separated into its antipodes with D- and L-di-p-toluoyltartaric acids. These antipodes and the racemic precursor have been evaluated (and found active) in two in vivo systems for their effects. The most potent of the three, (+)-8, has an ED50 of 7.13 mumol/kg for inhibition of spontaneous activity and 7.45 mumol/kg for antinociception compared to 4.44 and 4.81 mumol/kg, respectively, for (S)-(-)-nicotine. Compounds (-)-8 and 7 are about one-fourth as potent. Isomer (+)-8 has the 3aR,9bS configuration, the latter corresponding to (S)-(-)-nicotine as determined by X-ray crystallography. However, (+)-8 failed to compete for [3H]-nicotine binding, and its pharmacological effects were not blocked by mecamylamine. These bridged nicotine analogs either are binding to an as-yet-unidentified nicotinic receptor or they represent a novel class of non-nicotinic analgesics.
标题化合物8由异喹啉酮1合成（本文给出了其改进的制备方法），并用D-和L-二对甲苯甲酰酒石酸将其拆分为对映体。已在两种体内系统中评估了这些对映体及其外消旋前体的作用（并发现它们具有活性）。三者中活性最强的(+)-8，抑制自发活动的ED50为7.13 μmol/kg，抗伤害感受的ED50为7.45 μmol/kg，相比之下，(S)-(-)-尼古丁的相应值分别为4.44和4.81 μmol/kg。化合物(-)-8和7的活性约为其四分之一。异构体(+)-8具有3aR,9bS构型，通过X射线晶体学确定，后者与(S)-(-)-尼古丁相对应。然而，(+)-8未能竞争[3H]-尼古丁结合，其药理作用也未被美加明阻断。这些桥连尼古丁类似物要么与一种尚未确定的烟碱受体结合，要么代表一类新型的非烟碱类镇痛药。
