title: Fluorescent mu selective opioid ligands from a mixture based cyclic peptide library.
abstract: A positional scanning cyclic peptide library was generated using a penta-peptide thioester scaffold. Glycine was fixed at position R(1). Diaminopropionic acid was fixed at position R(3), with its γ-amino attaching to an anthraniloyl group. Positions R(2) and R(4) contained 36 L- and D- amino acids and position R(5) contained 19 L- amino acids. Cyclization was performed in a mixture of acetonitrile and 1.5 M aqueous imidazole solution (7:1 v/v) at room temperature for 5 days. No significant cross-oligomerization was detected under the cyclization conditions. The library was screened in a binding assay for mu opioid receptor, identifying the active amino acid mixture at each position. A total of 40 individual cyclic peptides were identified and synthesized by the combinations of the most active amino acid mixtures found at three positions 5 × 4 × 2. Two cyclic peptides exhibited high binding affinities to opioid receptor. The most active cyclic peptide in the library was yielded to have Tyr at R(2), D-Lys at R(4), and Tyr at R(5). Further investigation on this compound revealed the side chain-to-tail isomer to have greater binding affinity (14 nM) than the head-to-tail isomer (39 nM). Both isomers were selective for the mu-opioid receptor.
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida 34987, United States.
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Li
authors.forename: Colette T
authors.initials: CT
authors.lastname: Dooley
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Misler
authors.forename: Ginamarie
authors.initials: G
authors.lastname: Debevec
authors.forename: Marc A
authors.initials: MA
authors.lastname: Giulianotti
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Cazares
authors.forename: Laura
authors.initials: L
authors.lastname: Maida
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
mesh_terms: D005453:Fluorescence; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D008024:Ligands; D019151:Peptide Library; D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu