Alkylating Derivatives of Oxotremorine Have Irreversible Actions on Muscarinic Receptors

  • F. J. Ehlert
  • D. J. Jenden
Part of the Advances in Behavioral Biology book series (ABBI, volume 30)


The introduction of a β-chloroethylamino group into the structure of a drug has proven to be a successful means of developing irreversible ligands for α-adrenergic (10), muscarinic (6) and opiate receptors (2). Muscarinic agents would appear to be ideally suited for this type of chemical modification since the cationic aziridinium ring derived from a β-chloroethylmethylamino compound is structurally very similar to the trimethyl ammonium group of acetylcholine. This has been born out by the irreversible antagonist benzilylcholine mustard (6) which has proven to be a useful investigational tool in muscarinic receptor pharmacology. Recently, we and our colleagues have described some β-chloroethylamine derivatives of oxotremorine that are potent muscarinic agonists that bind irreversibly to the muscarinic receptor (3, 13, 14). The compounds, N-[4-(2-chloroethylmethylamino)-2-butynyl] -2-pyrrolidone (BM 123) and N-[4-(2-chloromethylpyrrolidino)-2-butynyl]-2-pyrrolidone (BM 130) (see Figure 1), cyclize spontaneously in neutral aqueous solutions to form aziridinium ions, which are responsible for their pharmacological effects (3, 13, 14). BM 123 and BM 130 stimulate contractions of the guinea pig ileum, and these effects are blocked by atropine, but not by hexamethonium (3, 13, 14). When injected into rats, BM 123 and BM 130 produce typical muscarinic effects including chromodacryorrhea, diarrhea, hypothermia, lacrimation, salivation and tremor. In this report, we describe some irreversible muscarinic receptor binding characteristics of BM 123 and BM 130, as well as the persistent inhibitory effect of BM 123 on acetylcholine release from the myenteric plexus of the guinea pig ileum.


Muscarinic Receptor Longitudinal Muscle Myenteric Plexus Acetylcholine Release ALKYLATING Derivative 
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  1. 1.
    Birdsall, N.J.M., Berrie, C.P., Burgen, A.S.V. and Hulme, E. C. (1980): In Receptors for Neurotransmitters and Peptide Hormones (eds) G. Pepeu, M.J. Kuhar and S.J. Enna, Raven Press, New York, pp. 107–116.Google Scholar
  2. 2.
    Caruso, T.P., Larson, D.L., Portoghese, P.S. and Takemori, A. E. (1980): J. Pharmacol. Exp. Ther. 213: 539–544.Google Scholar
  3. 3.
    Ehlert, F.J., Jenden, D.J. and Ringdahl, B. (1984): Life Sci. 34: 985–991.CrossRefGoogle Scholar
  4. 4.
    Ehlert, F.J., Roeske, W.R., Rosenberger, L.B. and Yamamura, H. I. (1980): Life Sci. 26: 245–252.CrossRefGoogle Scholar
  5. 5.
    Freeman, J.J., Choi, R.L. and Jenden, D.J. (1975): J. Neurochem. 24: 729–734.Google Scholar
  6. 6.
    Gill, E.W. and Rang, H.P. (1966): Mol. Pharmacol. 2: 284–297.Google Scholar
  7. 7.
    Jenden, D.J., Roch, M. and Booth, R.A. (1973): Analyt. Biochem. 55: 438–448.CrossRefGoogle Scholar
  8. 8.
    Kilbinger, H. (1978): In Cholinergic Mechanisms and Psychopharmacology (ed) D.J. Jenden, Plenum Press, New York,pp. 401–410.CrossRefGoogle Scholar
  9. 9.
    Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951): J. Biol. Chem. 193: 265–275.Google Scholar
  10. 10.
    Nickerson, M. and Gump, W.S. (1949): J. Pharmacol. Exp. Ther. 97: 25–47.Google Scholar
  11. 11.
    Paton, W.D.M. (1961): Proc. Roy. Soc. Lond. B. 154: 21–69.Google Scholar
  12. 12.
    Paton, W.D.M. and Vizi, E.S. (1969): Brit. J. Pharmacol. 35: 10–28.Google Scholar
  13. 13.
    Ringdahl, B., Ehlert, F.J. and Jenden, D.J. (1983): Fed. Proc. 42: 1148.Google Scholar
  14. 14.
    Ringdahl, B., Resul, B., Ehlert, F.J., Jenden, D.J. and Dahlbom, R. (1984): Mol. Pharmacol. 26: 170–179.Google Scholar
  15. 15.
    Yamamura, H.I. and Snyder, S.H. (1974): Proc. Natl. Acad. Sei. USA 71: 1725–1729.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • F. J. Ehlert
    • 1
  • D. J. Jenden
    • 1
  1. 1.Department of Pharmacology, School of Medicine and Brain Research InstituteUniversity of CaliforniaLos AngelesUSA

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