title: 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.
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.
authors.affiliation: Kyowa Hakko Kogyo Co. Ltd., Tokyo, Japan. hiroshi.kase@kyowa.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kase
authors.forename: S
authors.initials: S
authors.lastname: Aoyama
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: T
authors.initials: T
authors.lastname: Kanda
authors.forename: K
authors.initials: K
authors.lastname: Koga
authors.forename: N
authors.initials: N
authors.lastname: Koike
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kuwana
authors.forename: A
authors.initials: A
authors.lastname: Mori
authors.forename: J
authors.initials: J
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: M
authors.initials: M
authors.lastname: Ochi
authors.forename: M
authors.initials: M
authors.lastname: Saki
authors.forename: J
authors.initials: J
authors.lastname: Shimada
authors.forename: T
authors.initials: T
authors.lastname: Shindou
authors.forename: S
authors.initials: S
authors.lastname: Shiozaki
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Yanagawa
authors.forename: P J
authors.initials: PJ
authors.lastname: Richardson
authors.forename: P
authors.initials: P
authors.lastname: Jenner
authors.forename: P
authors.initials: P
authors.lastname: Bedard
authors.forename: E
authors.initials: E
authors.lastname: Borrelli
authors.forename: R A
authors.initials: RA
authors.lastname: Hauser
authors.forename: T N
authors.initials: TN
authors.lastname: Chase
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control; D005917:Globus Pallidus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D011323:Primates; D011687:Purines / Q000627:therapeutic use*; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011687:Purines; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; C111599:istradefylline; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine