1. Industry forum: Progress in pursuit of therapeutic A2A antagonists: The adenosine A2A receptor selective antagonist KW6002: Research and development toward a novel nondopaminergic therapy for Parkinson's disease
- Author
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Hiroshi, Kase, S, Aoyama, M, Ichimura, K, Ikeda, A, Ishii, T, Kanda, K, Koga, N, Koike, M, Kurokawa, Y, Kuwana, A, Mori, J, Nakamura, H, Nonaka, M, Ochi, M, Saki, J, Shimada, T, Shindou, S, Shiozaki, F, Suzuki, M, Takeda, K, Yanagawa, P J, Richardson, P, Jenner, P, Bedard, E, Borrelli, R A, Hauser, and T N, Chase
- Subjects
Primates ,Dyskinesia, Drug-Induced ,Parkinson's disease ,Receptor, Adenosine A2A ,medicine.drug_class ,Drug Evaluation, Preclinical ,Adenosine A2A receptor ,Motor Activity ,Globus Pallidus ,Medium spiny neuron ,Antiparkinson Agents ,Levodopa ,Mice ,Parkinsonian Disorders ,Dopamine ,medicine ,Animals ,Humans ,Oxidopamine ,gamma-Aminobutyric Acid ,Mice, Knockout ,Neurons ,Clinical Trials as Topic ,Receptors, Dopamine D2 ,Dopaminergic ,Antagonist ,Parkinson Disease ,medicine.disease ,Receptor antagonist ,Symptomatic relief ,Corpus Striatum ,Adenosine A2 Receptor Antagonists ,Rats ,Disease Models, Animal ,Purines ,Neurology (clinical) ,Psychology ,Neuroscience ,medicine.drug - Abstract
Research and development of the adenosine A 2A 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 A 2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A 2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A 2A receptors in the “dual” modulation of GABAergic synaptic transmission. Experiments with dopamine D 2 receptor knockout mice showed that A 2A receptors can function and anti-PD activities of A 2A 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 A 2A biologic research has been applied successfully to “proof of concept” clinical studies. The selective A 2A antagonist should provide a novel nondopaminergic approach to PD therapy.
- Published
- 2003