1. Enhanced responsiveness to nitric oxide, nitroxyl anions, and nitrergic transmitter by 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole in the rat anococcygeus muscle
Yan Che, Anthie Ellis, Chun Guang Li Nitric Oxide. 2005 Sep;13(2):118-24. doi: 10.1016/j.niox.2005.05.007.
The effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) on responses to sodium nitroprusside (SNP), S-nitroso-N-acetyl-penicillamine (SNAP), the nitroxyl anion donor Angeli's salt, and nitrergic nerve stimulation, as well as the release of NO from nitrergic nerves, were studied in the rat isolated anococcygeus muscle. YC-1 (1-100 microM) produced concentration-dependent relaxations in contracted muscles, which were partially but significantly reduced by the inhibitor of soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 1 and 10 microM). At a concentration that did not affect tissue tension, YC-1 (1 microM) significantly enhanced relaxations to SNP, SNAP, and Angeli's salt but did not affect relaxations to papaverine (10 microM). Nitrergic relaxations elicited by short periods (1 Hz for 10 s, 15 V) and long periods of EFS (5 Hz for 5 min, 15 V) were also enhanced by YC-1. YC-1 (100 microM), in an l-NAME and tetrodotoxin-insensitive manner, also increased the amount of NO detected in the organ bath media after the tissue was field stimulated (5 Hz for 5 min), which may have resulted from the electrolytic degradation of YC-1, as this effect was also seen in the absence of tissue. In summary, YC-1 enhanced relaxations to donors of NO, Angeli's salt, and nitrergic nerve stimulation in the rat anococcygeus muscle; however, the enhanced release of NO by YC-1 following nitrergic nerve stimulation was not a tissue-dependent effect.
2. Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy
Aubrie A Harland, Irina D Pogozheva, Nicholas W Griggs, Tyler J Trask, John R Traynor, Henry I Mosberg ACS Chem Neurosci. 2017 Nov 15;8(11):2549-2557. doi: 10.1021/acschemneuro.7b00284. Epub 2017 Aug 25.
In an effort to expand the structure-activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m-positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of 8c, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR.
