title: A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.
abstract: Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
authors: Huiping
authors: H
authors: Ding
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
authors: Paul W
authors: PW
authors: Czoty
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
authors: Norikazu
authors: N
authors: Kiguchi
authors: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom.
authors: Gerta
authors: G
authors: Cami-Kobeci
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
authors: Devki D
authors: DD
authors: Sukhtankar
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
authors: Michael A
authors: MA
authors: Nader
authors: Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom.
authors: Stephen M
authors: SM
authors: Husbands
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; mko@wakehealth.edu.
authors: Mei-Chuan
authors: 0000-0003-2436-4506
authors: MC
authors: Ko
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000819:agonists / Q000037:antagonists & inhibitors; D000818:Animals; D002047:Buprenorphine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D006801:Humans; D008024:Ligands; D018847:Opioid Peptides / Q000819:agonists / Q000037:antagonists & inhibitors; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D011323:Primates; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000473:pathology
chemical_list: C557645:2-(N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl)-3,3-dimethylpentan-2-ol; D000701:Analgesics, Opioid; D008024:Ligands; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D003042:Cocaine
keywords: N/OFQ peptide receptor; mu opioid peptide receptor; physical dependence; reinforcing effects; respiratory depression