title: Retooling manganese(III) porphyrin-based peroxynitrite decomposition catalysts for selectivity and oral activity: a potential new strategy for treating chronic pain.
abstract: Redox-active metalloporphyrins represent the most well-characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein, we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end, seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues, 7, 10, 12, 15, and 16a-c, have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a-c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition, oral administration of compound 7 (10-100 mg/kg, n=5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University, Edwardsville, Illinois 62026, United States.
authors.forename: Smita
authors.initials: S
authors.lastname: Rausaria
authors.forename: Mahsa M E
authors.initials: MM
authors.lastname: Ghaffari
authors.forename: Andrew
authors.initials: A
authors.lastname: Kamadulski
authors.forename: Kenny
authors.initials: K
authors.lastname: Rodgers
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shaw
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001897:Boronic Acids / Q000737:chemistry; D002351:Carrageenan; D002384:Catalysis; D059350:Chronic Pain / Q000188:drug therapy; D004563:Electrochemistry; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008345:Manganese; D008665:Metalloporphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D012584:Sciatic Nerve / Q000293:injuries; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry
chemical_list: D000700:Analgesics; D001897:Boronic Acids; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D008345:Manganese; D002351:Carrageenan; D013482:Superoxide Dismutase
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