How a single inversion. of configuration leads to a reversal of the binding mode:: Proposal of a novel arrangement of CCK2 ligands in their receptor, and contribution to the development of peptidomimetic or non-peptide CCK2 ligands

The implication of CCK2 receptors in crucial physiological functions has driven the search for synthetic ligands of this receptor. A notable rationale starting from CCK-4 (minimal endogenous CCK2 agonist), the 'dipeptoid' strategy, led to potent CCK2 antagonists exemplified by CI-988. However, careful examination of the literature enlightened several incompatibilities between the proposed recognition mode of the receptor by such compounds (or peptide analogues) and experimental data. Thus, we hypothesised that CCK2 'dipeptoid' antagonists bind the receptor in a mode opposite to that previously suggested. The reexamination of numerous published data, supported by the characterisation of new 'hybrid' compounds, brought out strong evidence that this 'reverse' mode truly characterises CCK2 'dipeptoid' antagonists. These findings renew the perspectives of further chemical development of CCK2 ligands, e.g. non-peptidic agonists. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.