title: Distribution of adenosine A(2A) receptor antagonist KW-6002 and its effect on gene expression in the rat brain.
abstract: A novel adenosine A(2A) receptor selective antagonist, KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], possesses antiparkinsonian activities in rodent and primate models. In the present study, we investigated the distribution of [14C]KW-6002 in forebrain after oral administration at pharmacologically effective doses. Also, we monitored the effects of the compound on preproenkephalin (PPE) and preprotachykinin (PPT) gene expression in rat striatum. The highest level of radioactivity was observed in the striatum after oral administration of [14C]KW-6002; 30 min after 0.1 and 0.3 mg/kg, the density values in the striatum were 2.45 and 2.43 times higher than those in a reference region (frontal cortex), respectively. At the dose of 3 mg/kg, p.o., the ratio was only 1.58 and the compound was distributed more extensively in the brain. The distribution pattern and intensity of radioactivity were maintained even 90 min after the administration of [14C]KW-6002. Oral administration of KW-6002 (0.3 and 3 mg/kg/day) to rats for 14 days reversed the increased gene expression of PPE in striatum that had been depleted of dopamine by prior treatment with 6-hydroxydopamine (6-OHDA). On the other hand, KW-6002 did not alter the decreased gene expression of PPT in 6-OHDA-treated rats. These results are the first to show directly that orally administered KW-6002 is distributed selectively to the striatum and that it modulates the activity of striatopallidal enkephalin-containing neurons but not striatonigral substance P-containing neurons.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co. Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Aoyama
authors.forename: Kumiko
authors.initials: K
authors.lastname: Koga
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mori
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Miyaji
authors.forename: Susumu
authors.initials: S
authors.lastname: Sekine
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kase
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Uchimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kuwana
mesh_terms: D000284:Administration, Oral; D018674:Adrenergic Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011498:Protein Precursors / Q000235:genetics; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D013565:Sympatholytics; D015320:Tachykinins / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D018674:Adrenergic Antagonists; D002250:Carbon Radioisotopes; D004745:Enkephalins; D011498:Protein Precursors; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D013565:Sympatholytics; D015320:Tachykinins; C044206:preprotachykinin; C111599:istradefylline; D016627:Oxidopamine; C033660:preproenkephalin