Abstract
Nicotinic acid, known as vitamin B3, is an effective lipid lowering drug and intense cutaneous vasodilator. This study reports the effect of 2-(1-adamantylthio)nicotinic acid (6) and its amide 7 and nitrile analog 8 on phenylephrine-induced contraction of rat thoracic aorta as well as antioxidative activity. It was found that the tested thionicotinic acid analogs 6-8 exerted maximal vasorelaxation in a dose-dependent manner, but their effects were less than acetylcholine (ACh)-induced nitric oxide (NO) vasorelaxation. The vasorelaxations were reduced, apparently, in both NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin (INDO). Synergistic effects were observed in the presence of L-NAME plus INDO, leading to loss of vasorelaxation of both the ACh and the tested nicotinic acids. Complete loss of the vasorelaxation was noted under removal of endothelial cells. This infers that the vasorelaxations are mediated partially by endothelium-induced NO and prostacyclin. The thionicotinic acid analogs all exhibited antioxidant properties in both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dismutase (SOD) assays. Significantly, the thionicotinic acid 6 is the most potent vasorelaxant with ED50 of 21.3 nM and is the most potent antioxidant (as discerned from DPPH assay). Molecular modeling was also used to provide mechanistic insights into the vasorelaxant and antioxidative activities. The findings reveal that the thionicotinic acid analogs are a novel class of vasorelaxant and antioxidant compounds which have potential to be further developed as promising therapeutics.
Highlights
Nicotinic acid, known as vitamin B3, has been used as a vitamin supplement in human and animal nutrition [1]
Results confirmed that the vasorelaxation of ACh was related to nitric oxide (NO)
8 possessed the highest dipole moment and the highest degree of asymmetric charge distribution. This investigation discloses novel vasorelaxants and antioxidants represented by 2-(1adamantylthio)nicotinic acid (6) and its amide 7 and nitrile analog 8
Summary
Nicotinic acid (niacin), known as vitamin B3, has been used as a vitamin supplement in human and animal nutrition [1]. Nicotinic acid is an effective lipid lowering drug and an intense cutaneous vasodilator which causes flushing [2,3]. It is referred to as a broad spectrum lipid drug [9] Such events are important therapeutic measures to reduce cardiovascular morbidity and mortality [9]. To discover novel vasodilators for medicinal applications, our rational molecular design is based on the documented activity of nicotinic acid derivatives and related compounds. In this context, 1-adamantyl-thionicotinic acid analogs 6-8 (Figure 2) are interesting target molecules. The target compounds 6-8 were prepared as described previously [14] and evaluated for vasorelaxant and antioxidative activities
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