Molecular Pharmacology, Vol 2, 352-359, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

The Influence of pH on the Muscarinic Action of Oxotremorine, Arecoline, Pilocarpine, and Their Quaternary Ammonium Analogs

¹ Department of Pharmacology, University of California, Los Angeles 90024

Oxotremorine, arecoline, pilocarpine, and their methiodides have been assayed for muscarinic activity on isolated guinea pig ileal segments using bethanechol as a reference compound over the pH range 6.2-8.7.

The relative activity of the tertiary amines decreased with increasing pH, while that of oxotremorine and arecoline methiodides was unaffected by pH. Pilocarpine methiodide was pharmacologically inert. The data were interpreted quantitatively using an iterative nonlinear regression procedure to fit an equation derived on the assumption that only the ionized forms of the compounds were active. A satisfactory fit for the five active compounds was obtained as judged by analyses of variance. The procedure also yielded estimates of the dissociation constants of the amines, which were close to those obtained by direct titration, although small significant differences were found.

All three tertiary amines were more active than the corresponding quaternary ammonium compounds, and the reasons for this anomaly are discussed. Evidence is presented to indicate that pilocarpine methiodide is 1,3-dimethyl substituted on the imidazole ring, and methylation of pilocarpine therefore yields a product which is not sterically analogous to the other two methiodides.

Note:
ACKNOWLEDGMENTS This work was supported by NIH grants NB 03007 and 5-F1-GM-22,905. Computing assistance was obtained from the Health Sciences Computing Facility, UCLA, sponsored by NIH grant FR-3. Grateful acknowledgment is made for the valuable consultation and advice of Mr. Joseph Steinborn, who carried out the programming and numerical calculations.

This article has been cited by other articles:

				K. W. Figueroa, M. T. Griffin, and F. J. Ehlert Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 331 - 342. [Abstract] [Full Text] [PDF]