title: Orally active opioid μ/δ dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice.
abstract: (E)-Methyl 2-((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12b-octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (7-hydroxymitragynine), a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7-Hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through μ-opioid receptors. In this study, we developed dual-acting μ- and δ-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in in vitro and in vivo assays. MGM-16 exhibited a high affinity for μ- and δ-opioid receptors, with K(i) values of 2.1 and 7.0 nM, respectively. MGM-16 showed μ- and δ-opioid full agonistic effects in a guanosine 5'-O-(3-[(35)S]thiotriphosphate) binding assay and in a functional test using electrically elicited guinea pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the μ-selective antagonist β-funaltrexamine hydrochloride (β-FNA) and by the δ-selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by β-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Chiba, Japan (K.Ma., N.M., K.T., S.H.); Department of Toxicology (K.Ma., M.N., T.S.) and Department of Pharmacology (K.Ma., M.N.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; Department of Molecular Structure and Biological Function, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (T.N., K.Mi., M.K., H.T.); and Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York (L.A.D.).
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Naotaka
authors.initials: N
authors.lastname: Muramatsu
authors.forename: Terumi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Kaori
authors.initials: K
authors.lastname: Misawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Kitajima
authors.forename: Kimihito
authors.initials: K
authors.lastname: Tashima
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takayama
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D007082:Ileum / Q000187:drug effects / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010812:Physical Stimulation; D011817:Rabbits; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000503:physiopathology; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism; D014110:Touch; D014649:Vas Deferens / Q000187:drug effects / Q000503:physiopathology
chemical_list: D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D046948:Secologanin Tryptamine Alkaloids; C587452:methyl 2-(3-ethyl-9-fluoro-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo(2,3-a)quinolizin-2-yl)-3-methoxyacrylate; C482678:7-hydroxymitragynine