title: 8-Substituted 2-alkynyl-N(9)-propargyladenines as A2A adenosine receptor antagonists.
abstract: Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N(9)-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
authors.affiliation: Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Endo
authors.affiliation: Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Deguchi
authors.affiliation: Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsunaga
authors.affiliation: Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Tomaya
authors.affiliation: Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan. Electronic address: k_yamada@yamasa.com.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000600992:8-bromo-2-(1-octyn-1-yl)-N9-propargyladenine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D043705:Receptor, Adenosine A2A; D014665:Vasodilator Agents; D000225:Adenine
keywords: Adenosine receptor; Agonist; Antagonist; Parkinson’s disease; Structure–activity relationship