Mixed-Ligand, Non-Nitrosyl Cu(II) Complexes as Potential Pharmacological Agents via NO Release

Abstract

Nitric oxide (NO) has recently been established as a key bioregulatory agent¹. Its multifaceted nature has been demonstrated in vascular relaxation, antiplatelet action, macrophage induced cytostasis and cytotoxicity, and neurotransmission. NO is produced endogenously from the amino acid L-arginine^2–3 by the enzyme NO synthase (Fig. 1). Several forms of this enzyme have been isolated. The NO produced can activate soluble guanylate cyclase, and thereby influence cellular concentration of another secondary messenger, cyclic GMP, resulting in different physiological responses. Another type of NO synthase, which is induced by activated macrophages and other cells, synthesizes NO which acts as a cytotoxic agent against tumor cells and bacteria. A number of cofactors are involved in the action of the enzyme, such as Ca²⁺/calmodulin, tetrahydrobiopterin, FMN, FAD and NADPH. NO synthase has high homology to cytochrome P₄₅₀ reductase.^4–5 Inhibitors of NO synthase activity include hemoglobin, the superoxide radical, and glucocorticoids. Analogues of L-arginine, where the guanidino NH₂ group has been replaced with groups such as MeNH (L-NMMA), Me (L-NIO), O₂N-NH (L-NA), or H₂N-NH (L-NAA) act as inhibitors⁶ of the endothelial NO synthase in vivo.