Motor effects of a dopamine stabilizer (GMC1111) in primate models of Parkinson and hemiparkinsonism

Abstract

The effects on motor behavior of a new potential dopamine stabilizer: 2-amino-6-( N, N-di- n-propylamino)thiazolo[4,5- f]indan (GMC1111) were investigated in common marmosets with 6-hydroxydopamine lesions within the median forebrain bundle (12 unilateral, 6 bilateral). GMC1111 was administered orally or subcutaneously (s.c.) to unilaterally 6-hydroxydopamine lesioned monkeys, either alone or together with s.c. injections of apomorphine (0.2 mg/kg) and the effect on rotational behavior was examined. GMC1111 (0.03–3.0 mg/kg) alone, orally or s.c., did not induce rotational behavior. When apomorphine and GMC1111 were injected simultaneously, rotations were nearly abolished in three monkeys with a baseline apomorphine-induced rotation rate below 13/min, whereas GMC1111 did not modify the rotations in three high-rotating animals (>17/min). Oral administration of GMC1111 (1.0 and 3.0 mg/kg) abolished the apomorphine-induced rotations in another six unilaterally dopamine-denervated monkeys, indicating a good oral bioavailability. A low dose of GMC1111 (0.3 mg/kg) administered s.c. to marmosets with bilateral nigrostriatal lesions produced a reduction of Parkinson symptoms of approximately the same degree as with levodopa/benserazide (15/3.75 mg/kg), while higher doses of GMC1111 were less effective. When levodopa/benserazide was administered together with various doses of GMC1111 (0.3–3.0 mg/kg), the levodopa-induced peak-dose dyskinesias were reduced with the highest dose of GMC1111 (3 mg/kg). Taken together, GMC1111 modifies dopaminergic activity in a normalizing direction. Parkinson symptoms, as well as levodopa-induced dyskinesias are both reduced. This suggests the arrival of another member of the new dopamine stabilizer family.