Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester.
A chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine<==>pyridinium salt redox system, was modified to include an activated carbamate ester. The dihydronicotinate moiety was chemically attached to the amino group of dopamine (DA) by acylation with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative, DA-CDSac. In vitro stability of the new compound was studied in phosphate buffers at mild acidic, physiological, and mild alkaline pH values. Oxidation studies showed facile conversion of the dihydronicotinate, DA-CDSac, is readily converted to the corresponding quaternary salt, both chemically and enzymatically. In vivo studies in rats did not detect sustained increases in brain levels of the quaternary salt after i.v. dosing with DA-CDSac. However, the new CDS appeared to change spontaneous locomotor activity in rats after i.v. administration which may be due to altered central DA neuronal activity.
Center for Drug Discovery, University of Florida, College of Pharmacy, Gainesville 32610.
F A
FA
Omar
H H
HH
Farag
N
N
Bodor
D000215:Acylation; D000478:Alkylation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004095:Dihydropyridines / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004355:Drug Stability; D004952:Esters; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009525:Niacin / Q000737:chemistry; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002219:Carbamates; D004095:Dihydropyridines; D004952:Esters; D009525:Niacin; C038806:1,4-dihydropyridine; D004298:Dopamine