Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437

Abstract

The selective dopamine D-2 receptor agonist N-0437 produced a rapid and dose-dependent reversal of motor deficits lasting 90–120 min following i.p. or oral administration of the racemate to MPTP-treated common marmosets. In contrast, topical application of (±)-, (+)- or (−)-N-0437 to the skin of MPTP-treated animals did not alter locomotor activity in the initial 4 h although other motor disabilities were reduced. However, 24 h following application of the racemate or the (−) enantiomer both locomotor activity and the other motor deficits induced by MPTP were improved. The increase in locomotor activity returned to basal values by 48–52 h following application of the racemate to the skin and by 72–76 h following administration of (−)-N-0437; the other motor deficits induced by MPTP were reduced for up to 72–76 h by both (±)- and (−)-N-0437. Application to skin of the (+) enantiomer produced no behavioural improvement or stimulation of locomotor activity. Transdermal administration of the active enantiomer of N-0437 may be of value in producing a prolonged reversal of parkinsonian motor deficits in man