CHOLECYSTOKININ PEPTIDOMIMETICS AS SELECTIVE CCK-B ANTAGONISTS - DESIGN, SYNTHESIS, AND IN-VITRO AND IN-VIVO BIOCHEMICAL-PROPERTIES

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioi d effects in animals. The clinical use of these compounds is criticall y dependent on their ability to cross the blood-brain barrier. In orde r to improve this property, new, peptoid-derived CCK-B antagonists, en dowed with high affinity, selectivity, and increased lipophilicity hav e been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mo use. Most of these compounds proved to be selective for the CCK-B rece ptor, the most potent analog, yltryptophanyl]-N-[2-(4-chlorophenyl)eth yl]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 [H-3]pBC 264, compound 26A was shown t o cross the blood-brain barrier (0.2%) after intraperitoneal administr ation in mice. This compound is therefore an interesting pharmacologic al tool to further elucidate the physiopathological role of endogenous CCK.