Calcium antagonist and antiperoxidant properties of some hindered phenols

• Published in: British journal of pharmacology 1993-09, Vol.110 (1), p.369-377
• Main Authors: Sgaragli, G.P., Valoti, M., Gorelli, B., Fusi, F., Palmi, M., Mantovani, P.
• Format: Article
• Language: English
• Subjects: 2,6‐di‐t‐butyl‐4‐methylphenol (BHT); 2‐t‐butyl‐4‐methoxyphenol (BHA); 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; Animals; antioxidant; Antioxidants - pharmacology; Barium - antagonists & inhibitors; Barium - pharmacology; Biological and medical sciences; Butylated Hydroxyanisole - pharmacology; Butylated Hydroxytoluene - pharmacology; calcium antagonist; Calcium Channel Blockers - pharmacology; Cardiovascular system; Free Radical Scavengers; Ileum - drug effects; In Vitro Techniques; Lipid Peroxidation - drug effects; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Miscellaneous; Muscle, Smooth - drug effects; Neuromuscular Depolarizing Agents - pharmacology; Pharmacology. Drug treatments; Phenol derivatives; Phenols - pharmacology; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1993.tb13819.x

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 Ca2+‐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 Ca2+‐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 μm Ca2+ or 500 μm 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 pIC50 (m) values ranging between 7.4 and 5.7. 7 Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic and antioxidant activity. Within this subgroup a linear and significant correlation was found between antispasmogenic 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.