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

作者：Adamska Bartlomiejczyk Anna; De Marco Rossella; Gentilucci Luca; Kluczyk Alicja; Janecka Anna^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(8): 2399-2405.

DOI：10.1016/j.bmc.2017.02.057

• Peptide synthesis
• Cyclization
• Receptor binding
• Opioid receptors
• Molecular mechanics

The study reports on a series of novel cyclopeptides based on the structure Tyr-[o-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 Phe(3)-Xaa(4) influences receptor selectivity through the control of the position of Phe(3) side chain. The results substantiate the use of the cycle-macrocyle scaffolds for fine-tuning receptor selectivity.

• 出版日期2017-4-15