E. Palomino, D. Kessel, J. Horwitz
Mar 1, 1989
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Influential Citations
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Journal
Journal of medicinal chemistry
Abstract
The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.