PEPTOID CCK RECEPTOR ANTAGONISTS - PHARMACOLOGICAL EVALUATION OF CCKA, CCKB AND MIXED CCKA/B RECEPTOR ANTAGONISTS

Several novel cholecystokinin (CCK) receptor ligands with differing degrees of receptor selectivity were characterised in both in vitro and in vivo models. In radioligand binding assays, the dipeptoid PD 135666 ((benzenebutanoic acid, beta-[[13-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1,(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino],[R-(R*,S*)]) selectively inhibited [I-125]Bolton Hunter CCK-8 binding to CCKB receptors in mouse cerebral cortex (CCKB IC50 = 0.1 nM) but was weaker as an inhibitor of CCKA receptor binding in the rat pancreas (IC50 = 26 nM). In contrast, its enantiomer PD 140548 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino],-[S-(R*,S*)) displayed the reverse selectivity (CCKA IC50 = 2.8 nM, CCKB IC50 = 260 nM). PD 142898 ({benzenebutanic acid, beta-[[3-(1H-indo1-3-yl)-2-methyl-2-[[[C(2-methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl}amino]-, [1R-[1 alpha[S*(R*)],2 beta]]) possessed nanomolar affinity for both receptor subtypes (CCKB IC50 = 4.2 nM, CCKA IC50 = 3.8 nM) whereas its corresponding enantiomer PD 142896 ((benzenebutanic acid, beta-[[3-(1H-indol-3-y])-2-methyl-2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-,[1R-[1 alpha[S* (R*)],2 beta]]) displayed 147-fold selectivity for the CCKA receptor (CCKA IC50 = 7.9 nM, CCKB IC50 = 1160 nM). The pyrazolidinone PD 141479 (trans-5-(2-chlorophenyl)-3-oxo-4-[henyl-N-[4-(trifluoromethyl)phenyl]-1-pyrazolidinecarboxamide) was found to interact selectively with the CCKB receptor (CCKB IC50 = 36 nM, CCKA IC50 = 1100 nM). PD 140548, PD 142896, PD 135666 and PD 142898 antagonised the CCKA receptor-mediated contraction of guinea pig gall bladder with respective pA(2) values of 7.2, 7.4, 6.6 and 8.5. In the rat elevated X-maze, PD 135666 and PD 141479, together with the mixed CCKA/B receptor antagonist PD 142898 produced anxiolytic effects with respective minimum effective doses (MEDs) of 0.01, 0.001 and 0.01 mg/kg s.c. Furthermore, the selective CCKB receptor antagonist CI-988 (0.01-1 mg/kg) and PD 142898 (0.001-0.1 mg/kg), dose dependently induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with respective MED values of < 0.01 and < 0.001 mg/kg s.c. In contrast, compounds with the CCKA selective profile were either inactive in the two behavioural models or showed activity only at doses of 1 mg/kg and above. These data suggest that the anxiolytic effects of CCK receptor antagonists parallel their affinity for the CCKB rather than the CCKA receptor.