Similar activity of mecamylamine stereoisomers in vitro and in vivo

Eur J Pharmacol. 2013 Nov 15;720(1-3):264-75. doi: 10.1016/j.ejphar.2013.10.018. Epub 2013 Oct 23.


A previous characterization of mecamylamine stereoisomers using nicotinic acetylcholine receptors expressed in Xenopus oocytes revealed only small differences between the activity of the R and S forms of mecamylamine. However, that work was limited in the breadth of receptor subtypes tested, especially in regard to the discrimination of high and low sensitivity receptors, which differ in the ratios of alpha and beta subunits. We report new data using subunit concatamers, which produce uniform populations of high-sensitivity or low-sensitivity receptors, as well as alpha2, alpha5, and alpha6-containing receptors, which were not studied previously. Consistent with previous studies, we found that beta4-containing receptors were most sensitive to mecamylamine and that the IC50 values for the inhibition of net charge were lower than for inhibition of peak currents. No large differences were seen between the activities of the mecamylamine isomers. Additionally, a previously reported potentiation of high-sensitivity α4β2 receptors by S-mecamylamine could not be reproduced in the oocyte system, even with mutants that had greatly reduced sensitivity to mecamylamine inhibition or when the selective agonist TC-2559 was used. In vivo studies suggested that the R-isomer might be somewhat more potent than the S isomer at blocking CNS effects of nicotine. Although the potency difference was no more than a factor of two, it is consistent with lower LD50 estimates previously reported for the R isomer. Our results significantly extend knowledge of the nicotinic acetylcholine receptor activity profile of mecamylamine and support the hypothesis that these effects are not strongly stereoisomer selective.

Keywords: Depression; Nicotine addiction; TC-2559; TC-5214; Tourette's syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Hot Temperature
  • Humans
  • Male
  • Mecamylamine / chemistry
  • Mecamylamine / pharmacology*
  • Mecamylamine / therapeutic use
  • Mice
  • Mice, Inbred ICR
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology*
  • Nicotinic Antagonists / therapeutic use
  • Oocytes / physiology
  • Pain / drug therapy
  • Protein Subunits / physiology
  • Receptors, Nicotinic / physiology*
  • Stereoisomerism
  • Xenopus laevis


  • Analgesics
  • Nicotinic Antagonists
  • Protein Subunits
  • Receptors, Nicotinic
  • Mecamylamine