Petrelli Riccardo, Scortichini Mirko, Kachler Sonja, Boccella Serena, Cerchia Carmen, Torquati Ilaria, Del Bello Fabio, Salvemini Daniela, Novellino Ettore, Luongo Livio, Maione Sabatino, Jacobson Kenneth A, Lavecchia Antonio, Klotz Karl-Norbert, Cappellacci Loredana
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
Institut für Pharmakologie and Toxikologie, Universität Würzburg , D-97078 Würzburg, Germany.
J Med Chem. 2017 May 25;60(10):4327-4341. doi: 10.1021/acs.jmedchem.7b00291. Epub 2017 May 5.
Structural determinants of affinity of N-substituted-5'-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N-cycloalkyl and 3-halobenzyl groups furnished potent dual acting AAR agonists and AAR antagonists. 4 was the most potent dual acting human (h) AAR agonist (K = 0.45 nM) and AAR antagonist (K = 0.31 nM) and highly selective versus A; 11 and 26 were most potent at both h and rat (r) AAR. All N-substituted-5'-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hAAR but agonists at the rAAR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (AAR antagonist blocked and AAR agonist strongly potentiated). N-Methyl-5'-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining AAR and AAR 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.
通过结合实验和分子模拟研究了N-取代-5'-C-(乙基四唑-2-基)腺苷和2-氯腺苷衍生物对腺苷受体(AR)亚型亲和力的结构决定因素。小的N-环烷基和3-卤苄基基团提供了强效的双重作用AAR激动剂和AAR拮抗剂。化合物4是最有效的双重作用人(h)AAR激动剂(K = 0.45 nM)和AAR拮抗剂(K = 0.31 nM)，对A具有高度选择性；化合物11和26对hAAR和大鼠(r)AAR均最有效。所有N-取代-5'-C-(乙基四唑-2-基)腺苷衍生物在hAAR上被证明是拮抗剂，但在rAAR上是激动剂。在小鼠福尔马林试验中评估了化合物11、22和26的镇痛作用(AAR拮抗剂阻断，AAR激动剂强烈增强)。N-甲基-5'-C-(乙基四唑-2-基)腺苷(22)最有效，抑制两个阶段，这与AAR和AAR激动剂联合使用时观察到的情况一致。这项研究首次证明了单一分子激活两条AR途径在这种急性疼痛模型中均有益处的优势。
