Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors.

TitleNovel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors.
Publication TypeJournal Article
Year of Publication2008
AuthorsVanderah TW, Largent-Milnes T, Lai J, Porreca F, Houghten RA, Menzaghi F, Wisniewski K, Stalewski J, Sueiras-Diaz J, Galyean R, Schteingart C, Junien J-L, Trojnar J, Rivière PJ-M
JournalEur J Pharmacol
Date Published2008 Mar 31
KeywordsAcetic Acid, Algorithms, Analgesics, Animals, Benzeneacetamides, Binding, Competitive, Dose-Response Relationship, Drug, Guanosine 5'-O-(3-Thiotriphosphate), Hot Temperature, Injections, Intravenous, Male, Mice, Mice, Inbred ICR, Oligopeptides, Opioid Peptides, Pain, Pain Measurement, Peripheral Nervous System, Postural Balance, Pyrrolidines, Radioligand Assay, Reaction Time, Receptors, Opioid, kappa

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.

Alternate JournalEur. J. Pharmacol.
PubMed ID18282565
Faculty Member Reference: 
Tally Largent-Milnes, PhD
Frank Porreca, PhD
Todd Vanderah, PhD