beta-Turned dipeptoids as potent and selective CCK(1) receptor antagonists

J Med Chem. 2000 Oct 5;43(20):3770-7. doi: 10.1021/jm000959x.

Abstract

To improve our knowledge of the bioactive conformation of CCK(1) antagonists, we previously described that replacement of the alpha-MeTrp residue of dipeptoids with the (2S,5S, 11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carbox ylate (IBTM) skeleton, a probed type II' beta-turn mimetic, led to restricted analogues (2S,5S,11bR,1'S)- and (2S,5S,11bR, 1'R)-2-(benzyloxycarbonyl)amino-5-[1'-benzyl-2'-(carboxy)ethyl]carbam oyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, 1a,b, showing high binding affinity and selectivity for CCK(1) receptors. In this report, we describe the synthesis and binding profile of new analogues of compounds 1 designed to explore the importance of the C-terminal residue and of the type of beta-turn on the receptor binding affinity and selectivity. Structure-affinity relationship studies show that a C-terminal free carboxylic acid and an S configuration of the Phe and betaHph residues are favorable for CCK(1) receptor recognition. Moreover, selectivity for this receptor subtype is critically affected by the beta-turn type. Thus, while compounds 15a and 16a, containing the (2S,5S,11bR)- and (2R,5R, 11bS)-IBTM frameworks, respectively, are both endowed with nanomolar affinity for CCK(1) receptors, restricted dipeptoid derivative 15a, incorporating the type II' IBTM mimetic, shows approximately 6-fold higher CCK(1) selectivity than analogue 16a, with the type II mimetic. From these results, we propose that the presence of a beta-turn-like conformation within the peptide backbone of dipeptoids could contribute to their bioactive conformation at the CCK(1) receptor subtype. Concerning functional activity, compounds 15a and 16a behave as CCK(1) receptor antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Dipeptides / chemistry*
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indolizines / chemical synthesis*
  • Indolizines / chemistry
  • Indolizines / metabolism
  • Molecular Conformation
  • Molecular Mimicry
  • Pancreas / metabolism
  • Protein Structure, Secondary
  • Radioligand Assay
  • Rats
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Receptors, Cholecystokinin / metabolism
  • Stereoisomerism

Substances

  • 2-(benzyloxycarbonyl)amino-5-(1'-carboxy-2'-phenylethyl)carbamoyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino(8,7-b)indole
  • Dipeptides
  • Indoles
  • Indolizines
  • Receptors, Cholecystokinin