Carboxymethylated tetrahydropyridoindoles as aldose reductase inhibitors: in vitro selectivity study in intact rat erythrocytes in relation to glycolytic pathway.
Oxidative stress and polyol pathway hypotheses are generally accepted in the etiology of diabetic complications. Recently, novel carboxymethylated pyridoindoles, structural analogues of the efficient chain-breaking antioxidant stobadine, were designed, synthesised and characterised as prospective aldose reductase inhibitors endowed with antioxidant activity. Of them (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (compound 1) and (2-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (compound 2) were found to be the most efficient inhibitors of aldose reductase with the corresponding IC50 values in a micromolar region. The aim of this work was to study cellular uptake of the novel pyridoindole derivatives and their effect on the complex metabolism of glucose in isolated rat erythrocytes under euglycaemic conditions. Glycolysis was shown to be the sole process responsible for the observed clearance of glucose. The compounds studied were avidly taken up by the cells, yet they did not significantly affect glucose consumption and lactate production nor did they affect osmotic fragility of the erythrocytes. On balance, the present experimental findings indicate that compounds 1 and 2, efficient inhibitors of aldose reductase, are selective in relation to the glycolytic pathway of glucose elimination. This conclusion supports current preclinical development of novel carboxymethylated tetrahydropyridoindoles as promising aldose reductase inhibitors for pharmacological prevention and treatment of diabetic complications.
Juskova
Maria
M
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
Snirc
Vladimir
V
Gajdosikova
Alena
A
Gajdosik
Andrej
A
Krizanova
Ludmila
L
Stefek
Milan
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009996:Osmotic Fragility / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D011108:Polymers; C024617:polyol; D013012:Sorbitol; D000449:Aldehyde Reductase; D005947:Glucose