d-argininamide--d-phenylalanyl-d-phenylalanyl-d-norleucyl-n-(4-pyridinylmethyl)- and Pain

Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid).. The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing.. Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007).. CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Electric Stimulation; Esophagus; Hot Temperature; Humans; Male; Monitoring, Physiologic; Muscle, Skeletal; Opioid Peptides; Oxycodone; Pain; Pain Measurement; Receptors, Opioid, kappa; Skin Physiological Phenomena; Young Adult

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH

Topics: Administration, Oral; Analgesics; Animals; Conditioning, Psychological; Locomotion; Male; Opioid Peptides; Pain; Rats; Rats, Sprague-Dawley; 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.

Topics: Acetic 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