Calcium antagonist and antiperoxidant properties of some hindered phenols.
1. The calcium antagonist and antioxidant activities of certain synthetic and natural phenols, related to BHA (2-t-butyl-4-methoxyphenol), were evaluated in rat ileal longitudinal muscle and in lipid peroxidation models respectively. 2. Compounds with a phenol or a phenol derivative moiety, with the exception of 2,2'-dihydroxy-3,-3'-di-t-butyl-5,5'-dimethoxydiphenyl (di-BHA), inhibited in a concentration-dependent manner the BaCl2-induced contraction of muscle incubated in a Ca(2+)-free medium. Calculated pIC50 (M) values ranged between 3.32 (probucol) and 4.96 [3,5-di-t-butyl-4-hydroxyanisole (di-t-BHA)], with intermediate activity shown by khellin < gossypol < quercetin < 3-t-butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6-di-t-butyl-4-methylphenol (BHT) and papaverine. 3. The Ca2+ channel activator Bay K 8644 overcame the inhibition sustained by nifedipine, BHA and BHT, while only partially reversing that of papaverine. 4. BHA, BHT, nifedipine and papaverine also inhibited in a concentration-dependent fashion CaCl2 contractions of muscle depolarized by a K(+)-rich medium. This inhibition appeared to be inversely affected by the Ca(2+)-concentration used. 5. The inhibitory effects of nifedipine, papaverine, BHA and BHT were no longer present when muscle contraction was elicited in skinned fibres by 5 microM Ca2+ or 500 microM Ba2+, suggesting a plasmalemmal involvement of target sites in spasmolysis. 6. Comparative antioxidant capability was assessed in two peroxyl radical scavenging assay systems. These were based either on the oxidation of linoleic acid initiated by a heat labile azo compound or on lipid peroxidation of rat liver microsomes promoted by Fe2+ ions. Across both model systems,di-t-BHA, NDGA, BHT, di-BHA, BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, with calculated pICso (M) values ranging between 7.4 and 5.7.7. Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic andantioxidant activity. Within this subgroup a linear and significant correlation was found betweenantispasmogenic activity and antioxidation. These bifunctional compounds were characterized by the presence of at least one hydroxyl group on the aromatic ring and a highly lipophilic area in the molecule.8. Di-t-BHA is proposed as a lead reference compound for future synthesis of new antioxidants combining two potentially useful properties in the prevention of tissue damage after ischaemia reperfusion injury.
Sgaragli
G P
GP
Istituto di Scienze Farmacologiche, Siena, Italy.
Valoti
M
M
Gorelli
B
B
Fusi
F
F
Palmi
M
M
Mantovani
P
P
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001464:Barium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016166:Free Radical Scavengers; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000975:Antioxidants; D002121:Calcium Channel Blockers; D016166:Free Radical Scavengers; D009467:Neuromuscular Depolarizing Agents; D010636:Phenols; D002084:Butylated Hydroxytoluene; D001464:Barium; D002083:Butylated Hydroxyanisole; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester