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.
Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold / Adamska-Bartłomiejczyk, Anna; De Marco, Rossella; Gentilucci, Luca; Kluczyk, Alicja; Janecka, Anna. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 25:8(2017), pp. 2399-2405. [10.1016/j.bmc.2017.02.057]
Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold
DE MARCO, ROSSELLA;GENTILUCCI, LUCA;
2017
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.