Motor effects of a dopamine stabilizer (GMC1111) in primate models of Parkinson and hemiparkinsonism.
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.
Klintenberg
Rebecka
R
Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, Biomedicum, SE-75124, Uppsala, Sweden.
Arts
Joris
J
Jongsma
Minke
M
Wikström
Håkan
H
Gunne
Lars
L
Andrén
Per E
PE
D000818:Animals; D002144:Callithrix; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D020820:Dyskinesias / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
C414214:6-amino-2-(N, N-di-n-propylamino)thiazolo(4,5-f)indan; D007189:Indans; D013844:Thiazoles; D016627:Oxidopamine; D004298:Dopamine