NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with 渭-Opioid Agonist Activity
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文摘
A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the 渭-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the 渭-opioid GPCR was predicated on the modulatory role of nitric oxide on 渭-opioid receptor function. Structure鈥揳ctivity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50 = 0.44 渭M), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent 渭-opioid binding affinity, Ki = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC50 = 0.34 渭M). This work represents a novel approach in the development of new analgesics for the treatment of pain.

Keywords:

nitric oxide; opioid; dual action; benzimidazole; NOS inhibitor; NOpiate; NOpioid

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