Abstract:
:Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.
journal_name
Neurologyjournal_title
Neurologyauthors
Kase H,Aoyama S,Ichimura M,Ikeda K,Ishii A,Kanda T,Koga K,Koike N,Kurokawa M,Kuwana Y,Mori A,Nakamura J,Nonaka H,Ochi M,Saki M,Shimada J,Shindou T,Shiozaki S,Suzuki F,Takeda M,Yanagawa K,Richardson PJ,Jenner Pdoi
10.1212/01.wnl.0000095219.22086.31subject
Has Abstractpub_date
2003-12-09 00:00:00pages
S97-100issue
11 Suppl 6eissn
0028-3878issn
1526-632Xjournal_volume
61pub_type
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