Antinociceptive effects of a new series of N6,5'-disubstituted adenosine derivatives

Adenosine receptors (ARs) belong to the family of G-protein coupled receptors (GPCRs). Four human ARs subtypes have been characterized, named A1, A2A, A2B and A3 ARs, that recognize adenosine and represent potential drug targets for a wide range of diseases. ARs have distinct distribution, signal transduction pathways, physiological effects, pharmacological properties and therapeutic application. [1] The A1AR is the best-characterized adenosine receptor subtype. Selective A1 adenosine receptor (A1AR) agonists have antinociceptive, antiarrhythmic, neuro- and cardioprotective effects and reduce lipolysis in adipose tissue and intraocular pressure in glaucoma. Our previous work discovered that combining the appropriate 5’- and N6-substitution in adenosine derivatives, highly selective human (h) A1AR agonists [2] or highly potent dual hA1AR agonists and hA3AR antagonists [3] can be obtained. The latter may be useful in the treatment of epilepsy and glaucoma. The substitution of the OH in 5’ of the sugar moiety of N6-substituted adenosine derivatives with a chlorine atom, brought to one of the most potent and selective hA1AR agonist (i.e. 5’-chloro-5’-deoxy-N6-(+)-endo-norbornyl- adenosine), while the replacement with a 5’-C-ethyl-tetrazolyl moiety maintained the high A1 potency, but restored also the A3AR affinity, leading to very potent dual hA1AR agonists and A3AR antagonists. [4] In order to explore new heterocycles in 5’-position of adenosine derivatives, a series of 5’- deoxy-5’-(3,5-dimethyl)-pyrazolyl-N6-substituted adenosine derivatives have been synthesized and tested in binding assays at all AR subtypes. Moreover, a molecular modeling and antinociceptive activities will be discussed. This work was supported by grants from the University of Camerino (Grant FAR 2014/15 FPI000044), and by the Italian MIUR funds (Grant 20094BJ9R7 and Grant 200928EEX4_004)