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CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule.


Motterlini, R; Sawle, P; Hammad, J; Bains, S; Alberto, R; Foresti, R; Green, C J (2005). CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB Journal, 19(2):284-286.

Abstract

Carbon monoxide (CO) is emerging as an important and versatile mediator of physiological processes to the extent that treatment of animals with exogenous CO gas has beneficial effects in a range of vascular- and inflammatory-related disease models. The recent discovery that certain transition metal carbonyls function as CO-releasing molecules (CO-RMs) in biological systems highlighted the potential of exploiting this and similar classes of compounds as a stratagem to deliver CO for therapeutic purposes. Here we describe the biochemical features and pharmacological actions of a newly identified water-soluble CO releaser (CORM-A1) that, unlike the first prototypic molecule recently described (CORM-3), does not contain a transition metal and liberates CO at a much slower rate under physiological conditions. Using a myoglobin assay and an amperometric CO electrode, we demonstrated that the release of CO from CORM-A1 is both pH- and temperature-dependent with a half-life of approximately 21 min at 37 degrees C and pH 7.4. In isolated aortic rings, CORM-A1 promoted a gradual but profound concentration-dependent vasorelaxation over time, which was highly amplified by YC-1 (1 microM) and attenuated by ODQ, a stimulator and inhibitor of guanylate cyclase, respectively. Similarly, administration of CORM-A1 (30 micromol/kg i.v.) in vivo produced a mild decrease in mean arterial pressure, which was markedly potentiated by pretreatment with YC-1 (1.2 micromol/kg i.v.). Interestingly, an inactive form of CORM-A1 that is incapable of releasing CO failed to promote both vasorelaxation and hypotension, thus directly implicating CO as the mediator of the observed pharmacological effects. Our results reveal that the bioactivities exerted by CORM-A1 reflect its intrinsic biochemical behavior of a slow CO releaser, which may be advantageous in the treatment of chronic conditions that require CO to be delivered in a carefully controlled manner.

Carbon monoxide (CO) is emerging as an important and versatile mediator of physiological processes to the extent that treatment of animals with exogenous CO gas has beneficial effects in a range of vascular- and inflammatory-related disease models. The recent discovery that certain transition metal carbonyls function as CO-releasing molecules (CO-RMs) in biological systems highlighted the potential of exploiting this and similar classes of compounds as a stratagem to deliver CO for therapeutic purposes. Here we describe the biochemical features and pharmacological actions of a newly identified water-soluble CO releaser (CORM-A1) that, unlike the first prototypic molecule recently described (CORM-3), does not contain a transition metal and liberates CO at a much slower rate under physiological conditions. Using a myoglobin assay and an amperometric CO electrode, we demonstrated that the release of CO from CORM-A1 is both pH- and temperature-dependent with a half-life of approximately 21 min at 37 degrees C and pH 7.4. In isolated aortic rings, CORM-A1 promoted a gradual but profound concentration-dependent vasorelaxation over time, which was highly amplified by YC-1 (1 microM) and attenuated by ODQ, a stimulator and inhibitor of guanylate cyclase, respectively. Similarly, administration of CORM-A1 (30 micromol/kg i.v.) in vivo produced a mild decrease in mean arterial pressure, which was markedly potentiated by pretreatment with YC-1 (1.2 micromol/kg i.v.). Interestingly, an inactive form of CORM-A1 that is incapable of releasing CO failed to promote both vasorelaxation and hypotension, thus directly implicating CO as the mediator of the observed pharmacological effects. Our results reveal that the bioactivities exerted by CORM-A1 reflect its intrinsic biochemical behavior of a slow CO releaser, which may be advantageous in the treatment of chronic conditions that require CO to be delivered in a carefully controlled manner.

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Additional indexing

Item Type:Journal Article, refereed
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:1 February 2005
Deposited On:11 Feb 2008 12:25
Last Modified:05 Apr 2016 12:20
Publisher:Federation of American Societies for Experimental Biology
ISSN:0892-6638
Publisher DOI:10.1096/fj.04-2169fje
PubMed ID:15556971
Permanent URL: http://doi.org/10.5167/uzh-1704

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