Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold

The study reports on a series of novel cyclopeptides based on the structure Tyr-[d-Lys-Phe-Phe-Asp]NH₂, a mixed mu and kappa opioid receptor agonist with low nanomolar affinity, in which Phe⁴ residue was substituted by cyclic amino acids, such as Pro or its six-membered surrogates, piperidine-2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). All derivatives exhibited high mu- and moderate delta-opioid receptor affinity, and almost no binding to the kappa-opioid receptor. Conformational analysis suggested that the cis conformation of the peptide bond Phe³-Xaa⁴ influences receptor selectivity through the control of the position of Phe³ side chain. The results substantiate the use of the cycle-macrocyle scaffolds for fine-tuning receptor selectivity.