Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- and (-)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-1H-pyrrolo- [3,2-h]isoquinoline, a structural analog of nicotine

Article abstract of 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 μmol/kg for inhibition of spontaneous activity and 7.45 μmol/kg for antinociception compared to 4.44 and 4.81 μmol/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.