CCK antagonist

CCK-B. Protease inhibitors that slow the degradation and inactivation of endogenous CCK promote satiety via CCK-A receptor. By contrast, the CCK-B receptor is important in mediating anxiety and panic attacks, and CCK antagonists are in clinical use to treat these symptoms. 

Various compounds bearing a carboxymethyl group at position 1 and a car-boxymethylamino function at position 3, including ACE inhibitors (27, 28), have been claimed as cholecystokinin (CCK)-antagonists [76-78]. Analogous compounds with a 3-hydroxy-2-oxopropyl moiety at position I are also claimed to be useful as antihypertensives and CCK antagonists [79],... 

Koenigsberg HW, Poliak CP, Fine J, Kakimia T (1994) Cardiac and respiratory activity in panic disorder effects of sleep and sleep lactate infusions. Am J Psychiatry 151 1148-1152 Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J (1995) A placebo-controlled trial of L-365,260, a CCK antagonist, in panic disorder. Biol Psychiatry 37 462-466 Le Mell4do JM, Bradwein J, Koszycki D, Bichet DG, BeUavance F (1998) The role of the P-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms. Biol Psychiatry 44 364-366... 

In the past decade many new examples have been described, mostly for amino acid derivatives using (substituted) benzaldehyde as a racemization catalyst. In Scheme 7.7 an application of this procedure on multi-kilogram scale from Merck Co is described for the asymmetric transformation of a benzodiazepinone in the synthesis of the CCK antagonist, L-364,718 (10),36 More recently, the Merck group also applied this method to other bendiazepinones.37... 

Niederau et al. (1989) compared the effects of CCK receptor antagonists on rat pancreatic secretion in vivo. Output of amylase in pancreatico-biliary secretion was measured after various doses of caerulein. The effects of high caerulein doses were dose-dependent inhibited by CCK-antagonists. 

Figure 10. An example of a shape-enhanced pharmacophore for a series of benzodiazepines as CCK antagonists. Terra incognita is shown transparently and forbidden regions are...

The discovery of the first nonpetide CCK antagonist, the natural product asperlicin, in 1985 (495) shifted the medicinal chemistry focus from peptides to small molecule antagonists (496,497).CCK-B receptors are the dominant isoform in the brain, and antagonists at this subtype are potential anxiolytics. Many CCK-B antagonists also modulate gastric acid secretion through peripheral CCK-B (gastrin) receptors. 

TABLE 15.14 Exploration of the Carboxyl Isosterism Possibilities in CCK Antagonists. a Series of... 

After the discovery of the potent CCK antagonistic activity of the natural compound asperlicin, the scientists from the Merck group prepared first some simple semi-synthetic derivatives. Then, recognizing in asperlicin the elements of a benzodiazepinone and a tetrahydroindole, they followed the hunch that these elements alone may confer some CCK antagonistic activity. This reasoning proved to be valid (Figure 16.36). 

Chang, R. S. L., Lotti, V. Y. Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide CCK antagonist. Proc. Natl. Acad. Sci. USA 1986, 83, 4923 926. 

CCK antagonists have not shown evidence for efficacy in chnical trials. Bioavailabihty is a problem with these compounds. 

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