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 m embers of a novel family of non-peptide cholecystokinin-B (CCKB) recep tor 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-te trahydro 1-quinolyl) carbonylmethyl] acetamide) and RP 72540 ((RS)-2-{ 3-{3-[N-(3-methoxy phenyl) N-(N-methyl N-phenyl-carbamoylmethyl) carba moylmethyl] ureido) phenyl) propionic acid) displayed nanomolar affini ty for guinea-pig, rat and mouse CCKB receptors labelled with [H-3]pCC K-8 or with the selective CCKB receptor ligand [H-3]pBC264. RP 69758 a nd RP 72540 showed selectivity factors in excess of 200 for CCKB versu s CCKA receptors. All three compounds had also high affinity for gastr in binding sites in the stomach. The ureido-acetamides behaved as pote nt antagonists of CCK-8-induced neuronal firing in rat hippocampal sli ces in vitro, a functional model of brain CCKB receptor mediated respo nses. RP 69758 is also a potent gastrin receptor antagonist in vivo th at dose dependently inhibits gastric acid secretion induced by i.v. in jection of pentagastrin in the rat. None of the three ureido-acetamide s, at concentrations up to 1 mu M, significantly blocked CCK-8-evoked contractions of the guinea-pig ileum in vitro, a CCKA receptor bioassa y. 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 i n mouse brain homogenate. However, the relative penetration of these u reido-acetamides into the forebrain after peripheral administration wa s below 0.01%. RP 71483 did not appear to cross the blood-brain barrie r in quantities sufficient to prevent [H-3]pCCK-8 binding at low doses , a property that makes it suitable for the exploration of the periphe ral versus central origin of the behavioural effects observed followin g systemic administration of CCK. RP 69758, RP 71483 and RP 72540 are highly potent and selective non-peptide CCK, receptor antagonists whic h are useful tools to explore the physiological functions of CCKB rece ptors.