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.
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.
Glassco
W
W
Department of Pharmacology and Toxicology, Medical College of Virginia-Virginia Commonwealth University, Richmond 23298.
Suchocki
J
J
George
C
C
Martin
B R
BR
May
E L
EL
D000700:Analgesics / Q000138:chemical synthesis; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003864:Depression, Chemical; D005731:Ganglionic Stimulants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists; D009619:Nociceptors / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000502:physiology; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D000700:Analgesics; D005731:Ganglionic Stimulants; D007546:Isoquinolines; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C084131:2,3,3a,4,5,9b-hexahydro-1-methyl-1H-pyrrolo(3,2-h)isoquinoline; D009538:Nicotine