Elucidating the structure-activity relationships of the vasorelaxation and antioxidation properties of thionicotinic acid derivatives.
Nicotinic acid, known as vitamin B(3), 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 N(G)-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 ED(50) 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.
Prachayasittikul
Supaluk
S
Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand. supaluk@swu.ac.th
Wongsawatkul
Orapin
O
Worachartcheewan
Apilak
A
Nantasenamat
Chanin
C
Ruchirawat
Somsak
S
Prachayasittikul
Virapong
V
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009525:Niacin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D013438:Sulfhydryl Compounds; D009536:Niacinamide; D009525:Niacin; C070820:thionicotinamide; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester