Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity.

• J Hughes

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• P Boden

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• B Costall

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• A Domeney

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• E Kelly

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• D C Horwell

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• J C Hunter

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• R D Pinnock

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

• G N Woodruff

  Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, United Kingdom.

Abstract

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with IC50 values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay and Ke values of 7.82 and 12.9 nM, respectively, in their blocking action on CCK responses in the rat lateral hypothalamic slice. PD134308 and PD135158 produced potent anxiolytic effects in the mouse black/white box test after either subcutaneous or oral administration. There was no evidence of the development of tolerance to the anxiolytic action of either PD134308 or PD135158 in mice treated twice daily for 7 days, nor was there any sign of withdrawal anxiogenesis after abrupt termination of this treatment. Both CCK-B antagonists were able to suppress the withdrawal anxiogenesis and produce an anxiolytic effect in mice previously made tolerant to diazepam. PD134308 and PD135158 produced potent anxiolytic effects in the rat elevated plus maze test and the rat social interaction test. The effects were comparable in magnitude to those seen with diazepam. However, unlike diazepam, PD134308 and PD135158 did not produce sedation. The CCK-B antagonists also showed powerful anxiolytic activity in the "marmoset human threat test." These results provide evidence of a selective role for CCK-B receptors in the control of anxiety. PD134308 and PD135158 are members of a class of anxiolytic agents that have a greatly improved profile compared with benzodiazepines or serotonin-related anxiolytics.

Journal

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 87 (17), 6728-6732, 1990-09

  Proceedings of the National Academy of Sciences

Keywords

• Multidisciplinary

Details

• CRID: 1360574095713340544
• NII Article ID: 80005429569
• NII Book ID: AA10808769
• DOI: 10.1073/pnas.87.17.6728
• ISSN: 10916490
• ISSN: 00278424
• ISSN: http://id.crossref.org/issn/00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.87.17.6728
• Data Source:
  • Crossref
  • CiNii Articles