Adenosine A_2A receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats

Abstract

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 μg/20 μl) of a selective adenosine A₂ receptor agonist CGS 21680 {2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine} 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.

Introduction

Current treatment of Parkinson's disease is based on dopamine replacement therapy. Nevertheless, benefits of this therapy often become compromised by long-term complications, including the onset of dyskinesia and wearing-off fluctuations (Marsden et al., 1982). Thus, a mechanism that targets a nondopaminergic receptor is an attractive alternative approach; adenosine A_2A receptor antagonists are candidates for such novel therapy Richardson et al., 1997, Kuwana et al., 1999.

Adenosine A_2A receptors are particularly abundant in the caudate-putamen, nucleus accumbens, and olfactory tubercle in several species Schiffmann et al., 1990, Dixon et al., 1996. In the caudate-putamen, adenosine A_2A receptor mRNA has been detected in γ-aminobutyric acid (GABA)ergic striatopallidal medium-sized spiny neurons (Schiffmann and Varderhaeghen, 1993; Fredholm et al., 1994, Mori et al., 1996). There is also functional evidence for the presence of adenosine A_2A receptor on striatal cholinergic nerve terminals Kawaguchi et al., 1995, Kurokawa et al., 1996, Richardson et al., 1997. These adenosine A_2A receptors have a profound influence on motor functions via the modulation of basal ganglia output pathways (Ochi et al., 2000).

We have recently developed orally active 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) (Shiozaki et al., 1999a). These adenosine A_2A receptor antagonists ameliorate motor dysfunctions of drug-induced catalepsy models and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or reserpine-induced Parkinsonian models in mice (Shiozaki et al., 1999b). More recently, we have reported that the combination of KW-6002 with dopaminergic drugs yields synergistic anti-Parkinsonian activity without an aggravation of dyskinesia in MPTP-treated common marmosets (Callithrix jacchus) Kanda et al., 1998a, Kanda et al., 1998b, Kanda et al., 2000.

In the present study, we investigated the effects of adenosine A_2A receptor antagonists KF17837 and KW-6002 in rats with a 6-hydroxydopamine lesion of the medial forebrain bundle, because this animal model of Parkinson's disease is one of the most reliable for the assessment of efficacy of candidate compounds (Ungerstedt and Arbuthnott, 1970). The study focuses on alterations of dopamine receptor agonist apomorphine or l-DOPA (l-3,4-dihydroxyphenylalanine) induced rotational behavior by KF17837 or KW-6002. We also investigated whether the potentiation of rotational behavior by these compounds is due to the increase of intensity or the prolongation of turning duration.