TY - JOUR
T1 - Antihypertensive Activity of Redox Derivatives of Tryptophan
AU - Pop, Emil
AU - Anderson, Wesley
AU - Prokai-Tatrai, Katalin
AU - Brewster, Marcus E.
AU - Bodor, Nicholas
AU - Fregly, Melvin
PY - 1990
Y1 - 1990
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0025326731&partnerID=8YFLogxK
U2 - 10.1021/jm00170a028
DO - 10.1021/jm00170a028
M3 - Article
C2 - 2374148
AN - SCOPUS:0025326731
SN - 0022-2623
VL - 33
SP - 2216
EP - 2221
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -