Ring-hydroxylated propranolol: synthesis and .beta.-receptor antagonist and vasodilating activities of the seven isomers

Abstract

Propranolol (Inderal; 1) is extensively metabolized in man. Metabolites of interest pharmacologically include ring-hydroxylated propranolols (1a-g). In order to identify these ring-oxidized products and to study the effect of hydroxyl position on biological activity, we have synthesized all seven isomers. With the exception of 1b and 1g, the desired compounds were prepared by alkylation of the respective methoxy-1-naphthols with epichlorohydrin and reaction of the resulting epoxide with isopropylamine. Cleavage og the methyl group in fused pyridine hydrochloride afforded 1a,c-f. 1g was prepared by the direct alkylation of 1,8-naphthalenediol (17) with epichlorohydrin, followed by reaction with isopropylamine. 1b was synthesized by treating 2-naphthol (9) with chlorine gas and then treating the resulting 1,1-dichloronaphthalen-2(1H)-one (10) with sodium allyl oxide. Acetylation of the hydroxy function and epoxidatrion of the allyl group, followed by relation with isopropylamine, gave 3'-hydroxy-4'-chloropropranolol (15). Dechlorination gave 1b. All of the racemic hydroxylated propranolols produced beta blockade and direct vasodilation in anesthetized dogs. The potency is strongly dependent upon the position of the hydroxyl group, i.e., 1e is 4 times as potent as 1 as a beta receptor antagonist, whereas 1a, 1b, and 1g are all significantly less potent than 1. For direct vasodilation, 1a and 1g are equipotent to 1, while 1b-f are much less potent. The potencies of the compounds were also compared with their 1-octanol/pH 7.4 buffer distribution coefficients; the direct vasodilating potency was found to increase with increasing lipophilicity, while the beta-adrenergic antagonist potency decreased.

Endotoxin-Mediated Disturbance of Hepatic Cytochrome P450 Function and Development of Endotoxin Tolerance in the Rat Model of Dextran Sulfate Sodium-Induced Experimental Colitis

“…DSS (molecular weight, 5000), LPS (Escherichia coli, serotype 0111:B4), polymyxin B sulfate, metronidazole, D-galactosamine hydrochloride, 4-nitrophenol, and 4-nitrocatechol were purchased from Wako Pure Chemicals (Osaka, Japan); testosterone, phenacetin, 4-acetamidophenol, and propranolol hydrochloride were from Sigma-Aldrich (St. Louis, MO); 2␣-, 6␤-, and 16␣-hydroxytestosterones were from Steraloids (Wilton, NH); 7-hydroxypropranolol was synthesized as hydrochlorides according to the method of Oatis et al (1981). Glucose 6-phosphate, glucose-6-phosphate dehydrogenase, and NADPH were purchased from Oriental Yeast Co., Ltd. All other chemicals and solvents used were of analytical grade.…”

Potent Antioxidant Properties of 4-Hydroxyl-propranolol

“…From a structural point of view, it is apparent that the presence of the HO group at the 4Ј position on the naphthalene moiety transforms the molecule into a vitamin E-like moiety with a phenol group attached to an aromatic resonance ring structure (naphthalene rings); the HO group probably confers the potent antioxidant activity in a manner similar to the phenol group of vitamin E (Burton and Ingold, 1981). With the HO group attached, 4HOP is more hydrophilic than its parent compound (Oatis et al, 1981), but it still retains a considerable degree of lipophilicity (Octanol/buffer partition coefficient ϳ3, compared with 18 for propranolol), which allows for its partitioning into cell membrane and LDL lipids. The observation (Fitzgerald and O'Donnell, 1971) that 4HOP provided a significant level of membrane stabilization activity in cardiac tissue supports this argument.…”

“…The propranolol metabolite 4-HOpropranolol (as hydrochloride) was a gift from Professor T. Walle (Medical University of South Carolina, Charleston, SC) and its purity was Ͼ97% (Oatis et al, 1981). LDL aliquots (L-2139) from human plasma, as well as most other chemicals were obtained from Sigma-Aldrich (St. Louis, MO).…”

Inactivation of Rat Cytochrome P450 2D Enzyme by a Further Metabolite of 4-Hydroxypropranolol, the Major and Active Metabolite of Propranolol.

“…4-OH-PL hydrochloride was supplied by the Sumitomo Chemical Co., Ltd. (Osaka, Japan). 5-OH-PL hydrochloride was synthesized according to the method of Oatis et al 18) (see chemical structures of the compounds used in Fig. 1).…”