Structural determinants of affinity of N⁶-substituted-5′-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N⁶-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A₁AR agonists and A₃AR antagonists. 4 was the most potent dual acting human (h) A₁AR agonist (K_i = 0.45 nM) and A₃AR antagonist (K_i = 0.31 nM) and highly selective versus A_2A; 11 and 26 were most potent at both h and rat (r) A₃AR. All N⁶-substituted-5′-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA₃AR but agonists at the rA₃AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A₃AR antagonist blocked and A₃AR agonist strongly potentiated). N⁶-Methyl-5′-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A₁AR and A₃AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.

中文翻译：

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探索N ^6-取代基在有效的双重作用5'- C-乙基四唑基腺苷衍生物中的作用：小鼠的合成，结合，功能测定和抗伤害感受作用∇

利用结合和分子模型研究了N ^6-取代的5'- C-（乙基四唑-2-基）腺苷和2-氯腺苷衍生物在腺苷受体（AR）亚型上的亲和力的结构决定因素。小的N ^6-环烷基和3-卤代苄基提供了有效的双作用A ₁ AR激动剂和A ₃ AR拮抗剂。4是最有效的双重作用人类（h）A ₁ AR激动剂（K _i = 0.45 nM）和A ₃ AR拮抗剂（K _i = 0.31 nM），相对于A _2A具有高度选择性；11和26在h和大鼠（r）A ₃ AR上均最有效。所有的N ^6-取代的5'- C-（乙基四唑-2-基）腺苷衍生物在hA ₃ AR处均被证明是拮抗剂，而在rA ₃ AR处则为激动剂。的镇痛11，22，和26在小鼠进行评价福尔马林试验（A ₃ AR拮抗剂阻止和A ₃ AR激动剂强烈强化）。如结合A ₁ AR和A ₃观察到的，N ^6-甲基-5'- C-（乙基四唑-2-基）腺苷（22）最有效，抑制了两个相。AR激动剂。这项研究首次证明了单个分子激活两条AR通路的优势，都可在这种急性疼痛模型中受益。