期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 8, 页码 2399-2405出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.02.057
关键词
Peptide synthesis; Cyclization; Receptor binding; Opioid receptors; Molecular mechanics
资金
- Medical University of Lodz [503/1-156-02/503-11-002]
- Medical University of Lodz for young researchers [502-03/1-156-02/502-14-240]
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. (C) 2017 Elsevier Ltd. All rights reserved.
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