Antihypertensive activity of redox derivatives of tryptophan.
The essential amino acid, tryptophan, has been shown to lower blood pressure in rats when administered orally or intravenously. In order to potentially enhance this action, a brain-targeting chemical delivery system (CDS) approach was applied to this compound. The CDS is based on a dihydropyridine----pyridinium ion redox system, chemically analogous to the naturally occurring NADH----NAD+ system. The dihydropyridine moiety containing carrier is chemically attached to the amino group by an amide-type bonding while the carboxylic acid functionality is esterified to various alcohols. Physicochemical studies of the new derivatives were performed. The determined chromatographic Rm values indicate an increased lipophilicity for the CDSs compared to the parent compound. Oxidation stability studies performed on selected compounds using a ferricyanide-mediated method showed that the CDSs are oxidized to the respective quaternary salt forms. Activity studies performed in deoxycorticosterone acetate induced hypertensive rats, demonstrated that the delivery system for tryptophan reduced blood pressure more efficiently for a longer time than did the parent compound.
Pop
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College of Pharmacy, University of Florida, J. Hillis Miller Health Center, Gainesville 32610.
Anderson
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Prókai-Tátrai
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Brewster
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ME
Fregly
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M
Bodor
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N
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003505:Cyclodextrins; D003900:Desoxycorticosterone; D004095:Dihydropyridines; D004337:Drug Carriers; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000959:Antihypertensive Agents; D003505:Cyclodextrins; D004095:Dihydropyridines; D004337:Drug Carriers; D011726:Pyridinium Compounds; D003900:Desoxycorticosterone; D014364:Tryptophan