The design and synthesis of novel beta-substituted amino acids, bicyclic dipeptide mimetics, and their incorporation into cholecystokinin/opioidchimeric peptides

Abstract

Peptide ligands and protein receptors play critical roles in the regulation of nearly every biological system. However, peptides are characteristically highly flexible and thus identifying the basic conformational elements necessary for recognition between a peptide ligand and it's receptor at the molecular level remains a formidable task. Great emphasis in peptide research has thus focused on the determination of the receptor-bound conformation adopted by bioactive peptides by synthesizing constrained analogues of the peptides. Knowledge of the three dimensional interaction between a peptide ligand and a receptor could be invaluable in understanding bioactivity and in the design of therapeutics. To determine the bioactive conformation of our novel chimeric peptides for the opioid and cholecystokinin receptors, constrained analogues were designed to limit the conformations that the peptides would adopt. In this regard, [5,5]- and [6,5]-bicyclic dipeptide mimetics were designed and synthesized to constrain a dipeptide unit and by extension limit the flexibility of the peptide. The bicyclic dipeptide mimetics were synthesized from precursors obtained by the beta-alkylation of aspartic acid and from the Kazmaier-Claisen rearrangement reaction. A protocol for the alkylkation of aspartic acid with allyl bromide, benzyl bromide, and benzyl disulfide was developed. The bicyclic dipeptide mimetics were then introduced into the peptides whose biological activity was evaluated at both the opioid and cholecystokinin receptors. The peptides showed good binding and functional activities at the CCK receptors, but low activities at the opioid receptors.