Antihypertensive Activity of Redox Derivatives of Tryptophan

Emil Pop, Wesley Anderson, Katalin Prokai-Tatrai, Marcus E. Brewster, Nicholas Bodor, Melvin Fregly

Research output: Contribution to journalArticle

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Abstract

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 Rmvalues 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. The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP+-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structuretoxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP+-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.

Original languageEnglish
Pages (from-to)2216-2221
Number of pages6
JournalJournal of Medicinal Chemistry
Volume33
Issue number8
DOIs
StatePublished - 1 Jan 1990

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Poisons
Tryptophan
Antihypertensive Agents
Oxidation-Reduction
NAD
Blood Pressure
Desoxycorticosterone
Essential Amino Acids
Guanidine
Microdialysis
Carboxylic Acids
Amides
Lactic Acid
Respiration
Acetates
Nitrogen
Perfusion
Salts
Alcohols

Cite this

Pop, Emil ; Anderson, Wesley ; Prokai-Tatrai, Katalin ; Brewster, Marcus E. ; Bodor, Nicholas ; Fregly, Melvin. / Antihypertensive Activity of Redox Derivatives of Tryptophan. In: Journal of Medicinal Chemistry. 1990 ; Vol. 33, No. 8. pp. 2216-2221.
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abstract = "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 Rmvalues 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. The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP+-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structuretoxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP+-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.",
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Pop, E, Anderson, W, Prokai-Tatrai, K, Brewster, ME, Bodor, N & Fregly, M 1990, 'Antihypertensive Activity of Redox Derivatives of Tryptophan', Journal of Medicinal Chemistry, vol. 33, no. 8, pp. 2216-2221. https://doi.org/10.1021/jm00170a028

Antihypertensive Activity of Redox Derivatives of Tryptophan. / Pop, Emil; Anderson, Wesley; Prokai-Tatrai, Katalin; Brewster, Marcus E.; Bodor, Nicholas; Fregly, Melvin.

In: Journal of Medicinal Chemistry, Vol. 33, No. 8, 01.01.1990, p. 2216-2221.

Research output: Contribution to journalArticle

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AU - Pop, Emil

AU - Anderson, Wesley

AU - Prokai-Tatrai, Katalin

AU - Brewster, Marcus E.

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AU - Fregly, Melvin

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