8-Substituted 2-alkynyl-N⁹-propargyladenines as A_2A adenosine receptor antagonists

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• 作者：Kazuki Endo ; Kazuki Deguchi ; Hirokazu Matsunaga ; Kota Tomaya ; Kohei Yamada ; ^{k_yamada@yamasa.com" class="auth_mail}
• 关键词：Adenosine receptor ; Agonist ; Antagonist ; Parkinson&rsquo ; s disease ; Structure&ndash ; activity relationship
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 June 2014
• 年：2014
• 卷：22
• 期：12
• 页码：3072-3082
• 全文大小：974 K

文摘

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 A_2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A_2A 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-N⁹-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.