CCK‐A Agonists: Endeavours involving structure‐activity relationship studies

The design cycle of peptidomimetics having CCK-A agonistic activity is discussed. The phases of this strategic approach are discussed briefly and results obtained either in our laboratories or by other groups are elaborated in this framework. Most of the CCK-A agonists prepared until recently still consist of six or more amino acid residues. Several conclusions can be drawn from studies in which one single amino acid has been exchanged against other residues. Studies involving the exchange of Tyr(SO3H) (amino acid 2) indicate that rather than the presence of the aromatic ring, the correct positioning of an acidic function is responsible for activity. The third amino acid (Met) probably acts as spacer residue. Amino acid 4 (Gly) can only be exchanged by D-amino acids containing small side chains (D-Ala). Replacement of Trp (amino acid 5) almost always results in decrease of actvity. Changes in position 6 indicate that the side-chain is involved in hydrophobic interactions with the receptor site and replacement of Asp (amino acid 7) demonstrates that the acidic function of the side chain is of importance for activity. The aromatic ring of amino acid 8 (Phe) may be substituted by a bulky alkyl or cycloalkyl moiety without considerable loss of activity. Isosteric replacements of protease-sensitive amide bonds enhancing the metabolic stability are permitted. Two new classes of cyclic peptides were found with conserved CCK-A activity. A start has been made with these peptides to determine the active CCK-A topology by means of molecular modeling and NMR studies.