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. 1994 Jun;112(2):666–670. doi: 10.1111/j.1476-5381.1994.tb13127.x

Evaluation of a series of novel CCKB antagonists using a functional assay in the rat central nervous system.

P R Boden 1, R D Pinnock 1, M C Pritchard 1, G N Woodruff 1
PMCID: PMC1910345  PMID: 8075886

Abstract

1. Electrophysiological recordings from rat ventromedial hypothalamus (VMH) in vitro have been used to compare the effects of novel chemical entities on CCKB receptor activation in the rat central nervous system. 2. Twenty compounds from three different chemical series were evaluated for their ability to reduce pentagastrin-induced increases in action potential firing rate. 3. All twenty compounds studies were found to be CCKB antagonists, with equilibrium constants spanning a concentration-range of several orders of magnitude. The rank order for their ability to block pentagastrin responses correlated well with values obtained for their relative affinities for the mouse cortex CCKB binding site. 4. It is concluded that the VMH preparation provides a good functional correlate to binding assays in the rodent central nervous system for a structurally diverse series of CCKB antagonists.

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Selected References

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  1. Boden P. R., Higginbottom M., Hill D. R., Horwell D. C., Hughes J., Rees D. C., Roberts E., Singh L., Suman-Chauhan N., Woodruff G. N. Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists. J Med Chem. 1993 Mar 5;36(5):552–565. doi: 10.1021/jm00057a005. [DOI] [PubMed] [Google Scholar]
  2. Boden P., Hill R. G. Effects of cholecystokinin and related peptides on neuronal activity in the ventromedial nucleus of the rat hypothalamus. Br J Pharmacol. 1988 May;94(1):246–252. doi: 10.1111/j.1476-5381.1988.tb11521.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bradwejn J., Koszycki D., Meterissian G. Cholecystokinin-tetrapeptide induces panic attacks in patients with panic disorder. Can J Psychiatry. 1990 Feb;35(1):83–85. doi: 10.1177/070674379003500115. [DOI] [PubMed] [Google Scholar]
  4. Chang R. S., Lotti V. J. Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4923–4926. doi: 10.1073/pnas.83.13.4923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dockray G. J. Immunochemical evidence of cholecystokinin-like peptides in brain. Nature. 1976 Dec 9;264(5586):568–570. doi: 10.1038/264568a0. [DOI] [PubMed] [Google Scholar]
  6. Dourish C. T., Ruckert A. C., Tattersall F. D., Iversen S. D. Evidence that decreased feeding induced by systemic injection of cholecystokinin is mediated by CCK-A receptors. Eur J Pharmacol. 1989 Dec 7;173(2-3):233–234. doi: 10.1016/0014-2999(89)90528-1. [DOI] [PubMed] [Google Scholar]
  7. Evans B. E., Bock M. G., Rittle K. E., DiPardo R. M., Whitter W. L., Veber D. F., Anderson P. S., Freidinger R. M. Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4918–4922. doi: 10.1073/pnas.83.13.4918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Evans B. E., Rittle K. E., Bock M. G., DiPardo R. M., Freidinger R. M., Whitter W. L., Lundell G. F., Veber D. F., Anderson P. S., Chang R. S. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J Med Chem. 1988 Dec;31(12):2235–2246. doi: 10.1021/jm00120a002. [DOI] [PubMed] [Google Scholar]
  9. Faris P. L., Komisaruk B. R., Watkins L. R., Mayer D. J. Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science. 1983 Jan 21;219(4582):310–312. doi: 10.1126/science.6294831. [DOI] [PubMed] [Google Scholar]
  10. Gibbs J., Young R. C., Smith G. P. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol. 1973 Sep;84(3):488–495. doi: 10.1037/h0034870. [DOI] [PubMed] [Google Scholar]
  11. Horwell D. C. Development of CCK-B antagonists. Neuropeptides. 1991 Jul;19 (Suppl):57–64. doi: 10.1016/0143-4179(91)90083-u. [DOI] [PubMed] [Google Scholar]
  12. Hughes J., Boden P., Costall B., Domeney A., Kelly E., Horwell D. C., Hunter J. C., Pinnock R. D., Woodruff G. N. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728–6732. doi: 10.1073/pnas.87.17.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Innis R. B., Corrêa F. M., Uhl G. R., Schneider B., Snyder S. H. Cholecystokinin octapeptide-like immunoreactivity: histochemical localization in rat brain. Proc Natl Acad Sci U S A. 1979 Jan;76(1):521–525. doi: 10.1073/pnas.76.1.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lotti V. J., Chang R. S. A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260. Eur J Pharmacol. 1989 Mar 21;162(2):273–280. doi: 10.1016/0014-2999(89)90290-2. [DOI] [PubMed] [Google Scholar]
  15. Watkins L. R., Kinscheck I. B., Mayer D. J. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984 Apr 27;224(4647):395–396. doi: 10.1126/science.6546809. [DOI] [PubMed] [Google Scholar]
  16. Wiesenfeld-Hallin Z., Xu X. J., Hughes J., Horwell D. C., Hökfelt T. PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7105–7109. doi: 10.1073/pnas.87.18.7105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Woodruff G. N., Hill D. R., Boden P., Pinnock R., Singh L., Hughes J. Functional role of brain CCK receptors. Neuropeptides. 1991 Jul;19 (Suppl):45–56. doi: 10.1016/0143-4179(91)90082-t. [DOI] [PubMed] [Google Scholar]

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