title: Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208.
abstract: An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA. jaldrich@ku.edu
authors.forename: Jane V
authors.initials: JV
authors.lastname: Aldrich
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Kulkarni
authors.forename: Sanjeewa N
authors.initials: SN
authors.lastname: Senadheera
authors.forename: Nicolette C
authors.initials: NC
authors.lastname: Ross
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Reilley
authors.forename: Shainnel O
authors.initials: SO
authors.lastname: Eans
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Ganno
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000737:chemistry / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; C540936:CJ 15,208; D008024:Ligands; D010456:Peptides, Cyclic; D017473:Receptors, Opioid, kappa; D010649:Phenylalanine; D000409:Alanine