posted on 2012-03-08, 00:00authored byPaul Renton, Brenda Green, Shawn Maddaford, Suman Rakhit, John S. Andrews
A novel series of benzimidazole designed multiple ligands
(DMLs)
with activity at the neuronal nitric oxide synthase (nNOS) enzyme
and the μ-opioid receptor was developed. Targeting of the structurally
dissimilar heme-containing enzyme and the μ-opioid GPCR was
predicated on the modulatory role of nitric oxide on μ-opioid
receptor function. Structure–activity relationship studies
yielded lead compound 24 with excellent nNOS inhibitory
activity (IC50 = 0.44 μM), selectivity over both
endothelial nitric oxide synthase (10-fold) and inducible nitric oxide
synthase (125-fold), and potent μ-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 μM). This work
represents a novel approach in the development of new analgesics for
the treatment of pain.