Retooling Manganese(III) Porphyrin-based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: a Potential New Strategy for Treating Chronic Pain

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2011 Nov 16

PMID 22082008

Citations 15

Authors

Smita Rausaria

Mahsa M E Ghaffari

Andrew Kamadulski

Kenny Rodgers

Leesa Bryant

Zhoumou Chen

Tim Doyle

Michael J Shaw

Daniela Salvemini

William L Neumann

Affiliations

Soon will be listed here.

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.

Citing Articles

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