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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.
AuthorsSmita Rausaria, Mahsa M E Ghaffari, Andrew Kamadulski, Kenny Rodgers, Leesa Bryant, Zhoumou Chen, Tim Doyle, Michael J Shaw, Daniela Salvemini, William L Neumann
JournalJournal of medicinal chemistry (J Med Chem) Vol. 54 Issue 24 Pg. 8658-69 (Dec 22 2011) ISSN: 1520-4804 [Electronic] United States
PMID22082008 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Analgesics
  • Boronic Acids
  • Metalloporphyrins
  • Peroxynitrous Acid
  • Manganese
  • Carrageenan
  • Superoxide Dismutase
Topics
  • Administration, Oral
  • Analgesics (chemical synthesis, chemistry, pharmacology)
  • Animals
  • Boronic Acids (chemistry)
  • Carrageenan
  • Catalysis
  • Chronic Pain (drug therapy)
  • Electrochemistry
  • Hyperalgesia (chemically induced, drug therapy)
  • Manganese
  • Metalloporphyrins (chemical synthesis, chemistry, pharmacology)
  • Mice
  • Neuralgia (drug therapy)
  • Peroxynitrous Acid (chemistry, metabolism)
  • Rats
  • Sciatic Nerve (injuries)
  • Structure-Activity Relationship
  • Superoxide Dismutase (chemistry)

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