A dihydropyridine conjugate which generates high and sustained levels of the corresponding pyridinium salt in the brain does not exhibit neurotoxicity in cynomolgus monkeys.
Many drugs can be selectively delivered to the brain by using a dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS). The interaction of these systems with central dopaminergic function was examined in this communication. Castrate female Sprague-Dawley rats when treated with a CDS for estradiol (i.e. 3-hydroxy-17 beta-[( (1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy) estra-1,3,5(10)-triene or E2CDS) exhibit sustained and profound suppression of serum levels of leuteinizing hormone (LH). Treatment of rats with pargyline (80 mg/kg) prior to E2CDS (2 mg/kg) did not mitigate the biological effectiveness of this estrogen indicating at least indirectly that monoamine oxidate (MAO) was not involved in the CDS activation. In a more direct examination, cynomolgus monkeys treated with various repeated doses of E2CDS (cumulative doses of 0.2-40.0 mg/kg) demonstrated neither impaired motor function nor depleted striatal dopamine concentrations. The latter parameter was measured using liquid chromatographic-electrochemical analysis. These experiments support the contention that the CDS is not neurotoxic and further strengthens the strict structure-activity requirements for MPTP-induced neurotoxicity.
Brewster
M E
ME
Center for Drug Design and Delivery, College of Pharmacy, JHMHC, University of Florida, Gainesville 32610.
Estes
K S
KS
Perchalski
R
R
Bodor
N
N
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000378:metabolism / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood; D008251:Macaca / Q000378:metabolism*; D008252:Macaca fascicularis / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D010293:Pargyline / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D004095:Dihydropyridines; D009498:Neurotoxins; D011726:Pyridinium Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D004958:Estradiol; D007986:Luteinizing Hormone; D010293:Pargyline; D008995:Monoamine Oxidase; D004298:Dopamine