Development of a Class of Selective Cholecystokinin Type B Receptor Antagonists Having Potent Anxiolytic Activity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 17; pp. 6728 - 6732
• Main Authors: Hughes, J., Boden, P., Costall, B., Domeney, A., Kelly, E., Horwell, D. C., Hunter, J. C., Pinnock, R. D., Woodruff, G. N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01-09-1990; National Acad Sciences
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Antianxiety agents; anxiety; anxiolytics; Benzodiazepines; Binding, Competitive; Brain; Callitrichinae; Cell Membrane - metabolism; Cerebral Cortex - metabolism; Cholecystokinin - analogs & derivatives; Cholecystokinin - pharmacology; Cholecystokinin receptors; Electrophysiology - methods; Humans; Indoles - pharmacology; Inhibitory concentration 50; Kinetics; Mazes; Meglumine - analogs & derivatives; Meglumine - pharmacology; Mice; Neurons; Pancreas - metabolism; Rats; Receptors; Receptors, Cholecystokinin - drug effects; Receptors, Cholecystokinin - metabolism; Social Behavior; Social interaction; Sorbitol - analogs & derivatives; Ventromedial Hypothalamic Nucleus - drug effects; Ventromedial Hypothalamic Nucleus - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.17.6728

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with IC50values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay and Kevalues 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.