1. Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold
- Author
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Luca Gentilucci, Rossella De Marco, Anna Janecka, Anna Adamska-Bartłomiejczyk, Alicja Kluczyk, Adamska-Bartłomiejczyk, Anna, De Marco, Rossella, Gentilucci, Luca, Kluczyk, Alicja, and Janecka, Anna
- Subjects
0301 basic medicine ,Agonist ,Macrocyclic Compounds ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Receptors, Opioid, mu ,Peptide synthesi ,Pharmaceutical Science ,Opioid ,Molecular Dynamics Simulation ,Ligands ,01 natural sciences ,Biochemistry ,κ-opioid receptor ,03 medical and health sciences ,Residue (chemistry) ,chemistry.chemical_compound ,delta ,Structure-Activity Relationship ,Receptors, Opioid, delta ,Drug Discovery ,Receptors ,medicine ,Side chain ,Peptide synthesis ,Peptide bond ,Molecular mechanics ,Receptor ,Molecular Biology ,Cyclization ,Opioid receptors ,Receptor binding ,Opioid Peptides ,010405 organic chemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Combinatorial chemistry ,0104 chemical sciences ,Molecular mechanic ,030104 developmental biology ,chemistry ,mu ,Molecular Medicine ,NIP ,Opioid receptor - 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.
- Published
- 2017