Synthesis and Testing of Neurological Produgs for the Gamma-Aminobutyric Acid System

Abstract

<p>The purpose of this work was to synthesize derivatives of a GABA agonist to be used as prodrugs. These compounds would be chemically liable and thus would not depend on enzymatic activation to release the parent drug.</p> <p>Two of the most potent GABA agonists, muscimoi and isoguvacine, were synthesized in 19% and 29% overall yield from propargyl chloride and isonicotinic acid, respectively. A series of prodrugs of muscimol, phenyl carbamate derivatives, were synthesized in 42-66% yields from the corresponding chloroformates. Depending on the substituents on the aromatic ring, a wide range of hydrolysis rates (2.8 to 380 mins) and partition coefficients (0.05 to over 15) were observed for these carbamates. These prodrugs were evaluated as sedatives and anticonvulsants. All carbamates with partition coefficients greater than 0.1 induced dose-dependent sedation which was found to increase with increasing partition coefficient and with increasing hydrolysis rate. Sedation times as long as 12 hours were observed in mice. While one of these carbamates, the p-carboethoxyphenyl carbamate, showed no inhibition of seizures induced by GABA antagonists, a significant delay (about 80%) in the onset of these seizures was observed. Muscimol itseIf had no effect on these antagonist-induced seizures.</p> <p>Some carbamates radiolabelled in the muscimol portion were administered to mice i.p. and the amount of free [³H]-muscimol in the brain was determined after 1 hour. The amounts of muscimol found ranged from 2.3 to 10.5 nmols/brain. These quantities paralleled the amount of sedation produced by these carbamates.</p> <p>A phenyl acetamide of muscimol with a partition coefficient identical to a sedative carbamate was prepared, as a non-labile counter-part to the labile carbamate. No sedation was observed for this acetamide even at high doses. Thus it appears that intact carbamates are not responsible for the sedative effects. • However, seven per cent of a radiolabelled form of this acetamide was found in the brain, indicating that agents with similar partition coefficients have ready access to the brain by passive diffusion.</p>