PHARMACOLOGICAL PROPERTIES OF UREIDO-ACETAMIDES, NEW POTENT AND SELECTIVE NONPEPTIDE CCK(B)/GASTRIN RECEPTOR ANTAGONISTS

We present here the pharmacological properties of 3 ureido-acetamide members of a novel family of non-peptide cholecystokinin-B (CCKB) receptor antagonists. RP 69758 (3-{3-[N-(N-methyl N-phenyl-carbamoylmethyl) N-phenylcarbamoylmethyl] ureido) phenylacetic acid), RP 71483 ((E)-2-[3-(3-hydroxyiminomethyl phenyl) ureido] N-(8-quinolyl) N-[(1,2,3,4-tetrahydro 1-quinolyl) carbonylmethyl] acetamide) and RP 72540 ((RS)-2-{3-{3-[N-(3-methoxy phenyl) N-(N-methyl N-phenyl-carbamoylmethyl) carbamoylmethyl] ureido) phenyl) propionic acid) displayed nanomolar affinity for guinea-pig, rat and mouse CCKB receptors labelled with [H-3]pCCK-8 or with the selective CCKB receptor ligand [H-3]pBC264. RP 69758 and RP 72540 showed selectivity factors in excess of 200 for CCKB versus CCKA receptors. All three compounds had also high affinity for gastrin binding sites in the stomach. The ureido-acetamides behaved as potent antagonists of CCK-8-induced neuronal firing in rat hippocampal slices in vitro, a functional model of brain CCKB receptor mediated responses. RP 69758 is also a potent gastrin receptor antagonist in vivo that dose dependently inhibits gastric acid secretion induced by i.v. injection of pentagastrin in the rat. None of the three ureido-acetamides, at concentrations up to 1 mu M, significantly blocked CCK-8-evoked contractions of the guinea-pig ileum in vitro, a CCKA receptor bioassay. In ex vivo binding studies, i.p. administration of RP 69758 and RP 72540 resulted in a dose-dependent inhibition of [H-3]pCCK-8 binding in mouse brain homogenate. However, the relative penetration of these ureido-acetamides into the forebrain after peripheral administration was below 0.01%. RP 71483 did not appear to cross the blood-brain barrier in quantities sufficient to prevent [H-3]pCCK-8 binding at low doses, a property that makes it suitable for the exploration of the peripheral versus central origin of the behavioural effects observed following systemic administration of CCK. RP 69758, RP 71483 and RP 72540 are highly potent and selective non-peptide CCK, receptor antagonists which are useful tools to explore the physiological functions of CCKB receptors.