SYNTHESIS AND BIOLOGICAL PROPERTIES OF NEW CONSTRAINED CCK-B ANTAGONISTS - DISCRIMINATION OF 2 AFFINITY STATES OF THE CCK-B RECEPTOR ON TRANSFECTED CHO CELLS

To improve our knowledge of the bioactive conformation of CCK-B antago nists, we have developed a new series of constrained dipeptoids whose synthesis and biochemical properties are reported here. These compound s, of general structure )carbonyl]-alpha-methyltryptophanyl-(4-X)-prol ine, were designed by introducing a cyclization in the structure of th e previously described CCK-B/peptoid antagonist RB 210, alpha-methyltr yptophanyl]-N-(2-phenylethyl)glycine (Blommaert et al. J. Med. Chem. 1 993, 36, 2868-2877), by means of a five-membered ring. Structure-affin ity relationship studies showed that an R configuration of Trp-C-alpha and a cis configuration of the pyrrolidine substituents were favorabl e for receptor recognition. The most potent compounds of this new seri es had similar affinities for the CCK-B receptor as RB 210 and proved to be far more efficient in inhibiting inositol phosphate production i n CHO cells stably transfected with rat brain CCK-B receptor, with IC5 0 values approaching those of the commonly used antagonists L-365,260 and PD-134,308. Moreover, binding studies performed using transfected CHO cells showed that two affinity states of the CCK-B receptor can be discriminated by some of these compounds which also have different bi ological profiles and are therefore highly interesting tools for the b iochemical and pharmacological characterization of CCK-B receptor hete rogeneity.