title: Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors.
abstract: Kappa-(kappa) opioid receptors are widely distributed in the periphery and activation results in antinociception; however supraspinal acting kappa-agonists result in unwanted side effects. Two novel, all d-amino acid, tetrapeptide kappa-opioid receptor agonists, FE 200665 and FE 200666, were identified and compared to brain penetrating (enadoline) and peripherally selective (asimadoline) kappa-agonists as potential analgesics lacking unwanted central nervous system (CNS) side effects. In vitro characterization was performed using radioligand binding and GTP gamma S binding. Antinociception was evaluated in both mice and rats. Rotarod tests were performed to determine motor impairment effects of the kappa-agonists. FE 200665 and FE 200666 showed high affinity for human kappa-opioid receptor 1 (Ki of 0.24 nM and 0.08 nM, respectively) and selectivity for human kappa-opioid receptor 1 (human kappa-opioid receptor 1/human mu-opioid receptor/human delta-opioid receptor selectivity ratios of 1/16,900/84,600 and 1/88,600/>1,250,000, respectively). Both compounds demonstrated agonist activity in the human kappa-opioid receptor 1 [35S]GTP gamma S binding assay (EC50 of 0.08 nM and 0.03 nM) and resulted in dose-related antinociception in the mouse writhing test (A50: 0.007 and 0.013 mg/kg, i.v., respectively). Markedly higher doses of FE 200665 and FE 200666 were required to induce centrally-mediated effects in the rotarod assay (548- and 182-fold higher doses, respectively), and antinociception determined in the mouse tail-flick assay (>1429- and 430-fold fold higher doses, respectively) after peripheral administration supporting a peripheral site of action. The potency ratios between central and peripheral activity suggest a therapeutic window significantly higher than previous kappa-agonists. Furthermore, FE 200665 has entered into clinical trials with great promise as a novel analgesic lacking unwanted side effects seen with current therapeutics.
authors.affiliation: Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA. vanderah@u.arizona.edu <vanderah@u.arizona.edu>
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Tally
authors.initials: T
authors.lastname: Largent-Milnes
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: Frédérique
authors.initials: F
authors.lastname: Menzaghi
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wisniewski
authors.forename: Jacek
authors.initials: J
authors.lastname: Stalewski
authors.forename: Javier
authors.initials: J
authors.lastname: Sueiras-Diaz
authors.forename: Robert
authors.initials: R
authors.lastname: Galyean
authors.forename: Claudio
authors.initials: C
authors.lastname: Schteingart
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Junien
authors.forename: Jerzy
authors.initials: J
authors.lastname: Trojnar
authors.forename: Pierre J-M
authors.initials: PJ
authors.lastname: Rivière
mesh_terms: D019342:Acetic Acid; D000465:Algorithms; D000700:Analgesics; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006358:Hot Temperature; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay; D011930:Reaction Time / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; C432025:FE 200666; D009842:Oligopeptides; D018847:Opioid Peptides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C432024:D-argininamide, D-phenylalanyl-D-phenylalanyl-D-norleucyl-N-(4-pyridinylmethyl)-; C045444:U 69593; D019342:Acetic Acid