Riccardo Petrelli1, Mirko Scortichini1, Sonja Kachler2, Serena Boccella3, Carmen Cerchia4, Ilaria Torquati1, Fabio Del Bello1, Daniela Salvemini5, Ettore Novellino4, Livio Luongo3, Sabatino Maione3, Kenneth A Jacobson6, Antonio Lavecchia4, Karl-Norbert Klotz2, Loredana Cappellacci1. 1. School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy. 2. Institut für Pharmakologie and Toxikologie, Universität Würzburg , D-97078 Würzburg, Germany. 3. Section of Pharmacology "L. Donatelli", Department of Experimental Medicine, University of Campania "L. Vanvitelli" , 80138 Naples, Italy. 4. Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II , 80131 Naples, Italy. 5. Department of Pharmacology and Physiology, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States. 6. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
Abstract
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 (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 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.
Structural determinants of affinity of N6-substituted-5'-C-(ethyltetrazol-2-yl)adenosine and n class="Chemical">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 (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 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 mouseformalin 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.
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