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Enkephalin is a competitive antagonist of cholecystokinin in the gastrointestinal tract, as predicted from prior conformational analysis

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Abstract

Prior calculations based on ECEPP (Empirical Conformational Energies for Peptides Program) of the low energy minima for cholecystokinin (CCK) and Met-enkephalin have demonstrated that significant structural features of these two peptides are identical. This result suggested the possibility that Met-enkephalin, as well as other enkephalin analogues of similar structure, could associate with receptors for CCK. To test this theoretical result, we examined the ability of Met-enkephalin and its analogues to bind to peripheral CCK receptors in the rat gastrointestinal tract; in particular, we measured the ability of the opiate peptide to inhibit the effects of CCK in a physiological assay system which we have previously characterized: CCK-induced contraction of the isolated rat pyloric sphincter. We find that Met-enkephalin is an antagonist of the CCK-8-induced contraction, with a IC50 of 110 nM. Furthermore, antibodies against CCK were found to cross-react with Met-enkephalin and its analogues in a manner which suggests a distinct structure-activity relationship. These experimental results strongly support the theoretical results of conformational analysis showing structural similarity between enkephalin and CCK. They further suggest that enkephalins could modulate the response of CCK systems under physiological conditions.

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Authors and Affiliations

  1. Westchester Division, Department of Psychiatry, E. W. Bourne Laboratory, New York Hospital-Cornell University Medical Center, 21 Bloomingdale Road, 10605, White Plains, NY

    Randall B. Murphy, Linda H. Schneider, James Gibbs & Gerard P. Smith

  2. Department of Chemistry and Center for Neural Sciences, New York University, 10003, New York, NY

    Randall B. Murphy, Matthew R. Pincus & James M. Chen

  3. Department of Pathology, S.U.N.Y.-Health Science Center, 750 East Adams St, 13210, Syracuse, NY

    Matthew R. Pincus & Daryll C. Dykes

  4. Department of Pharmacology, St. Louis University School of Medicine, 1402 So. Grand Bl., 63104, St. Louis, Mo

    Margery Beinfeld

Authors
  1. Randall B. Murphy
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  2. Matthew R. Pincus
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  3. Margery Beinfeld
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  4. Daryll C. Dykes
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  5. James M. Chen
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  6. Linda H. Schneider
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  7. James Gibbs
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  8. Gerard P. Smith
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Murphy, R.B., Pincus, M.R., Beinfeld, M. et al. Enkephalin is a competitive antagonist of cholecystokinin in the gastrointestinal tract, as predicted from prior conformational analysis. J Protein Chem 11, 723–729 (1992). https://doi.org/10.1007/BF01024973

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  • DOI: https://doi.org/10.1007/BF01024973

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