Novel CCK-B receptor agonists: diketopiperazine analogues derived for CCK4 bioactive conformation

Recently, we proposed a CCK-B agonist bioactive conformation characterized by an 'S' shape of the peptidic backbone which was derived from structure-activity relationships and conformational analysis of CCK4 (Trp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp-Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a small linker to Asp-Phe-NH2. Some of these compounds displayed good affinities and selectivities for the CCK-B receptor. The results are discussed in terms of size, hydrophobicity and spatial orientation of the side-chains on the diketopiperazine ring. The most potent ligand exhibited potent and full CCK-B receptor agonist properties in promoting the hydrolysis of inositol phosphates (EC50 = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, it increased gastric acid secretion measured in anesthetized rats on i.v. administration. These compounds provide a rigid template for the design of non-peptide CCK-B agonists, by modification of the remaining peptide moiety.