Cyclic mu-opioid receptor ligands containing multiple N-methylated amino acid residues.
In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor. This peptide was also shown to be a full agonist, while the other analogs failed to activate the mu opioid receptor. Results of molecular docking studies provided rationale for the explanation of binding properties on a structural basis.
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Anna
A
Adamska-Bartłomiejczyk
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Anna
A
Janecka
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary.
Márton Richárd
MR
Szabó
Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Maria Camilla
MC
Cerlesi
Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Girolamo
G
Calo
Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
Alicja
A
Kluczyk
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary.
Csaba
C
Tömböly
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary. Electronic address: borics.attila@brc.mta.hu.
Attila
A
Borics
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D003500:Cyclization; D006801:Humans; D008024:Ligands; D008745:Methylation; D062105:Molecular Docking Simulation; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000701:Analgesics, Opioid; D008024:Ligands; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu
Binding studies; Cyclic peptides; Docking; Enzymatic stability; Functional assays; N-Methylated amino acids; Opioid receptors