New substituted MECA derivatives as potent and selective agonists for the human adenosine A3 receptor

Adenosine A3 receptor (AA3R) is involved in a variety of key physiological processes such as release of inflammatory mediators and inhibition of tumour necrosis factor-α production. Its agonists have cardioprotective and cerebroprotective potential and also may have a role in the treatment of asthma as anti-inflammatory and immunosuppressive agents and in cancer therapy as cytostatic and chemoprotective compounds [1, 2]. On this base, the design and synthesis of potent and elective AA3R agonists could be helpful in providing tools for the further characterisation and evaluation of the physiopathological role of this receptor and for the development of new drugs. In previous works, we reported that 5′-N-methylcarboxamidoadenosine (MECA) derivatives bearing in 2-position (ar) alkynyl chains and in N6-position a methoxy group showed good affinity and different degree of selectivity for the human AA3R subtype [3]. We reported also that the introduction of a methyl group in N6-position of 2-phenylethynyladenosine favoured the interaction with the human AA3R [4]. Aimed at improving AA3R affinity and selectivity, we designed and synthesised 2-aralkynyl-N6-methylMECA derivatives, which were then evaluated in radioligand binding studies and in functional assays performed in CHO cells, stably transfected with human ARs. Results proved that the new compounds behave as AA3R full agonists and are endowed with sub-nanomolar affinity and notable selectivity for this AR subtype [5]. Molecular modelling studies were carried out to get a rationalisation of the high selectivities of the presented molecules for the human AA3R by using the recently solved AA2AR crystal structure as template for homology modelling studies.