SYNTHESIS, OPTICAL RESOLUTION, ABSOLUTE-CONFIGURATION, AND PRELIMINARY PHARMACOLOGY OF (+)-CIS-2,3,3A,4,5,9B-HEXAHYDRO-1-METHYL-1H-PYRROLO-[32-H]ISOQUINOLINE AND (-)-CIS-2,3,3A,4,5,9B-HEXAHYDRO-1-METHYL-1H-PYRROLO-[3,2-H]ISOQUINOLINE, A STRUCTURAL ANALOG OF NICOTINE

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 [H-3]-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.