Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats.
The effects of novel adenosine A(2A) receptor antagonists KF17837 ((E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methyl-3, 7-dihydro-1H-purine-2,6-dione) and KW-6002 ((E)-1,3-diethyl-8-(3, 4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione), on rotational behavior induced by apomorphine or L-DOPA (L-3, 4-dihydroxyphenylalanine) were investigated in rats with unilateral 6-hydroxydopamine lesions. Both KF17837 and KW-6002 slightly induced rotational behavior per se. However, KF17837 and KW-6002 significantly increased the total counts of turning induced by apomorphine at doses of 3 mg/kg, p.o. and 10 mg/kg, p.o., and at doses of 1 mg/kg, p.o. and higher, respectively. KF17837 and KW-6002 also potentiated the rotational behavior induced by L-DOPA at a dose of 3 mg/kg, p.o. Furthermore, i.c.v. injection (10 microg/20 microl) of a selective adenosine A(2) receptor agonist CGS 21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoaden osine] partially prevented the rotational behavior induced by apomorphine and this inhibition was reversed by KW-6002 (1 mg/kg, p.o.). The increase in total counts of apomorphine-induced turning by the adenosine A(2A) receptor antagonists seems to be mainly attributable to prolongation of turning duration rather than enhancement of intensity. These results suggest that these adenosine A(2A) receptor antagonists may be useful to ameliorate shortening in the duration of dopaminergic drug response in patients with advanced Parkinson's disease.
Koga
K
K
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co. Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, 411-8731, Shizuoka, Japan.
Kurokawa
M
M
Ochi
M
M
Nakamura
J
J
Kuwana
Y
Y
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine / Q000009:adverse effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D014970:Xanthines / Q000494:pharmacology*
D015259:Dopamine Agents; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D014970:Xanthines; C081198:KF 17837; C111599:istradefylline; D007980:Levodopa; D016627:Oxidopamine; D001058:Apomorphine