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

Abstract

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with ICSO values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay andKe values of7.82 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 prorfle compared with benzodiazepines or serotonin-related anxiolytics.

Characterization of CCK receptors in a novel smooth muscle preparation from the guinea‐pig stomach by use of the selective antagonists CI‐988, L‐365,260 and devazepide

“…The CCKA receptor has a high affinity for CCK-8S and a 7000 fold lower affinity for gastrin I (Hughes et al, 1990). This receptor subtype is present on a number of peripheral tissues and cells particularly in the alimentary tract (Zetler, 1984;Innis & Snyder, 1980) but also occurs in some highly localized regions of the brain (Hill et al, 1987) for example in dorsal raphe neurones .…”

“…The CCKB/gastrin receptor is recognised by gastrin, CCK-8S, CCK-8US and CCK-4 with approximately equal affinity (Hughes et al, 1990). Currently the CCKB and gastrin receptor are pharmacologically indistinguishable (Freidinger, 1989).…”

“…Currently the CCKB and gastrin receptor are pharmacologically indistinguishable (Freidinger, 1989). The CCKB receptor exists predominantly in the central nervous system (Hughes et al, 1990) while the gastrin receptor is found primarily in the alimentary canal, for example on gastric parietal cells, pancreatic acinar cells and smooth muscle cells (Grider & Makhlouf, 1987;Cherner et al, 1988).…”

Effects of Cholecystokinin Peptides and GV 150013, a Selective CholecystokininB Receptor Antagonist, on Electrically Evoked Endogenous GABA Release from Rat Cortical Slices

“…Several studies indicate that CCK possesses anxiogenic properties (Harro et al, 1993;Rex et al, 1994;Bourin et al, 1996;Biró et al, 1997) and induces panic attacks in human volunteers (Bradwejn et al, 1990), whereas CCK B antagonist shows potent anxiolytic effects in rodent and primate models of anxiety (Hughes et al, 1990;Singh et al, 1991). On the other hand, it is well known that GABA neurotransmission plays a relevant role in anxiety and panic disorders (Abelson and Nesse, 1990), and an increase in GABA release leads to an anxiolytic effect (Costa et al, 1975;Tallman et al, 1978).…”

“…To date, two subtypes of CCK receptors, named CCK A and CCK B , have been characterized with the majority of brain receptors being of the latter type (Innis and Snyder, 1980;Bourin et al, 1996). Much evidence indicates that activation of both CCK receptors produces a variety of physiological and behavioral effects, and neuronal CCK has been proposed to play a significant role in a wide range of central actions, such as analgesia (Baber et al, 1989;Crawley and Corwin, 1994), memory processes (Kadar et al, 1981;Fekete et al, 1982;Bohme and Blanchard, 1992;Crawley and Corwin, 1994), anxiety (Hughes et al, 1990;Harro et al, 1993;Bourin et al, 1996), and the etiopathogenesis of mental disorders (Crawley, 1991). Thus, potential therapeutic properties of selective CCK receptor ligands have been suggested.…”