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 Phe4residue 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-Xaa4influences receptor selectivity through the control of the position of Phe3side chain. The results substantiate the use of the cycle-macrocyle scaffolds for fine-tuning receptor selectivity.
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Anna
A
Adamska-Bartłomiejczyk
Department of Chemistry 'G. Ciamician', University of Bologna, via Selmi 2, 40126 Bologna, Italy.
Rossella
R
De Marco
Department of Chemistry 'G. Ciamician', University of Bologna, via Selmi 2, 40126 Bologna, Italy.
Luca
L
Gentilucci
Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
Alicja
A
Kluczyk
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
Anna
A
Janecka
D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D018847:Opioid Peptides / Q000737:chemistry* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D047028:Macrocyclic Compounds; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
Cyclization; Molecular mechanics; Opioid receptors; Peptide synthesis; Receptor binding