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

Abstract

The implication of CCK(2) receptors in crucial physiological functions has driven the search for synthetic ligands of this receptor. A notable rationale starting from CCK-4 (minimal endogenous CCK(2) agonist), the 'dipeptoid' strategy, led to potent CCK(2) 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 CCK(2) '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 CCK(2) 'dipeptoid' antagonists. These findings renew the perspectives of further chemical development of CCK(2) ligands, e.g. non-peptidic agonists.