Synthesis and biological properties of new constrained CCK-B antagonists: discrimination of two affinity states of the CCK-B receptor on transfected CHO cells.
To improve our knowledge of the bioactive conformation of CCK-B antagonists, we have developed a new series of constrained dipeptoids whose synthesis and biochemical properties are reported here. These compounds, of general structure N alpha-[(2-adamantyloxy)carbonyl]-alpha-methyltryptophanyl-(4 -X)-proline, were designed by introducing a cyclization in the structure of the previously described CCK-B/peptoid antagonist RB 210, N-[N-[(2-adamantyloxy)carbonyl]-DL-alpha-methyltryptophanyl] -N-(2-phenylethyl)glycine (Blommaert et al. J. Med. Chem. 1993, 36, 2868-2877), by means of a five-membered ring. Structure-affinity relationship studies showed that an R configuration of Trp-C alpha and a cis configuration of the pyrrolidine substituents were favorable for receptor recognition. The most potent compounds of this new series had similar affinities for the CCK-B receptor as RB 210 and proved to be far more efficient in inhibiting inositol phosphate production in CHO cells stably transfected with rat brain CCK-B receptor, with IC50 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 biological profiles and are therefore highly interesting tools for the biochemical and pharmacological characterization of CCK-B receptor heterogeneity.
Bellier
B
B
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D1500, CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
McCort-Tranchepain
I
I
Ducos
B
B
Danascimento
S
S
Meudal
H
H
Noble
F
F
Garbay
C
C
Roques
B P
BP
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006224:Cricetinae; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D034444:Peptoids; D011392:Proline / Q000031:analogs & derivatives; D011487:Protein Conformation; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014162:Transfection
D004151:Dipeptides; D034444:Peptoids; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011392:Proline; D000218:Adamantane