CCK-B antagonist

Wilson, J, Watson, WP and Little, HJ (1998) CCK(B) antagonists protect against anxiety-related behaviour produce by ethanol withdrawal, measured using the elevated plus-maze. Psychopharmacology 137 121-131. 

Gilbert, J.D., Hand, E.L., Yuan, A.S., Olah, TV. and Covey T.R. (1992) Determination of L-365,260, a new cholecystokinin receptor (CCK-B) antagonist, in plasma by liquid chromatography/atmospheric pressure chemical ionisation mass sectrometry Biological Mass Spectrometry, 21 (2), 63-68. 

CCK8 concentrations were found to be lower in panic patients than in normal control subjects (Brambilla et al. 1993) and the CCK-B receptors were hyper-sensitive in panic disorders (Akiyoshi et al. 1996). Accordingly, CCK-B receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans (Radu et al. 2002). Clinical trials, however, have provided inconclusive data about the anxiolytic potential of CCK-B antagonists (Shlik et al. 1997). 

Cl-988 has been found to reduce the behavioral stress in marmosets exposed to a human threat [Hughes et al. 1990]. L-365,260 can antagonize the behavioral effects of exposition to the odor of a cat in rats and suppress the behavioral reaction of mice to the calls of an owl, an effect also found with LY 288513 (Hendrie and Dourish 1994]. Thus, evidence suggests an anxiolytic activity of CCK-B antagonists. The activity seems more evident in etho-logically based models of anxiety than in conflict-based tests and does not follow a linear dose-dependent relationship but rather a bell-curve one. Also, most studies point to a selectivity of CCK-B antagonists, but not CCK-A antagonists, for anxiolytic effects. 

The panicogenic effects of CCK-B agonists and the ability of CCK-B antagonists to block this effect raise the question of therapeutic efficacy of CCK-B antagonists on spontaneous panic attacks. Thus far, the only clinical trial carried out is inconclusive. Kramer and colleagues [1995] used a multicenter, placebo-controlled, double-blind trial to investigate the efficacy of L-365,260 [30 mg four times a day] in patients with panic disorder with or... 

Hendrie CA, Dourish CT Effects of cholecystokinin tetrapeptide and the CCK-B antagonist LY 288513 in a putative model of panic in the mouse, in Ethology and Psychopharmacology. Edited by Cooper SJ, Hendrie CA. Chichester, England, Wiley, 1994, pp 110-132... 

Powell KR, Barrett JE Evaluation of the effects of PD 134308 (Cl-988), a CCK-B antagonist, on the punished responding of squirrel monkeys. Neuropeptides 19 (suppl) 75-78, 1991... 

Cholecystokinin (CCK) The tetrapeptide CCK causes more panic attacks when infused into patients with panic disorder than it does in normal volunteers, which suggests increased sensitivity of the brain type of CCK receptor, known as CCK-B. Unfortunately, in early investigations CCK-B antagonists did not appear to be effective for panic disorder. Nevertheless, agents with novel pharmacological mechanisms of action are sometimes evaluated for their potential antipanic actions by testing whether they can block CCK-induced panic attacks. 

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. 

CP-212,454 (129) (520) is representative of a series of benzazepin-2-ones that possess high affinity and CCK-B selectivity. (129) was selected for clinical study as an anxiolytic but, not uncommonly among CCK-B antagonists. 

Other CCK-B antagonist series to show some anxiolytic activity include the quinazo-lines, also derived from asperlicin, developed at Eli Lilly (530), and hybrids" (531-534), which combine important components of the 1,4-benzodiazepine series (the phenylurea) and the quinazolines. 

In a recent example, aryl-carboxylic solubilization was used to solubilize core-modified porphyrins. Solubilizing aryl carboxylic functions were also replaced by their tetra-zole or 1,2,4-oxadiazolone bioisosteres in the design of second generation, benzodiazepine-derived, CCK-B antagonists (Figure 38.2). °... 

Bock, M. G., DiPardo, R. M., Mellin, E. C., Newton, R. C., Veber, D. F, Freedman, S. B. Second-generation benzodiazepine CCK-B antagonists. Development of subnanomolar analogs with selectivity and water solubility. J. Med. Chem. 1994, 37, 722-724. 

Synthesis and Structure-Activity Relationship of New 1,5 Benzodiazepine CCK-B Antagonists... 

Evidence from animal studies have suggested the potential utility of CCK-B antagonists in the treatment of CNS disorders such as anxiety and panic, with a seemingly specific advantage of a better safety profile over marketed anxiolytics, at least on the basis of the preclinical data. 

The purpose of this study was to identify new CCK-B antagonists endowed with a better pharmacological profile, both in terms of potency and selectivity, than existing antagonists (e.g. L-365,260). As a result of our studies, a novel series of 1,5-benzodiazepines bearing either ureidic or carbamic side-chains at C-3 were discovered. ... 

As a result of this evaluation, GV150013 (fig 4) has emerged as a potent and selective CCK-B antagonist and has been progressed into development. Its profile is given below. 

After an initial evaluation of l,5-benzodiazepine-l,4-diones as potential CCK-B antagonists, we restricted our interest to compounds bearing an aryl substituent at N-5 in conjunction with... 

Gaviraghi G, Cassari P, Corsi M, Curotto G, Donati D, Feriani A, Finch H, Finizia G, Pentassuglia G, Polinelli S, Ratti E, Reggiani A, Tarzia G, Tedesco G, Tranquillini ME, Trist DG, Ursini A Synthesis and structure-activity relationship of new 1,5-benzodiazepine CCK-B antagonists... 

Horwell, D.C., Hughes, J., Hunter, J., Pritchard, M., Richardson, R., Roberts, E. Woodruff, G. (1991) Rationally designed dipeptoid analogues of CCK. Alpha-methyltryptophan derivatives as highly selective and orally active gastrin and CCK-B antagonists with potent anxiolytic properties, J. Med. Own. 34, 404—414. 

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