Cholecystokinin Peptidomimetics as Selective CCK-B Antagonists: Design, Synthesis, and in Vitro and in Vivo Biochemical Properties

Article abstract of DOI:10.1021/jm00072a005

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK₄-induced panic attacks in humans and to potentiate opioid effects in animals.The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier.In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed.The affinity and selectivity of these compounds have been cheracterized in vitro and in vivo using guinea pig, rat, and mouse.Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N--D-α-methyltryptophanyl>-N-<2-(4-chlorophenylethyl)glycine (26A), having a K_i value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (K_i CCK-A/K_i CCK-B = 174).Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol.Using competition experiments with the specific CCK-B ligand <3H>pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2percent) after intraperitoneal administration in mice.This compound is therefore an interesting pharmacological tool to further elucidate the physicopathological role of endogenous CCK.