Anales RANF

P2. P HARMACOLOGY AND B IOCHEMISTRY OF P1 R ECEPTORS P.09 2-ARYLADENINE DERIVATIVES AS POTENT SCAFFOLDS FOR A 1 , A 3 AND DUAL A 1 /A 3 ADENOSINE RECEPTOR ANTAGONISTS: SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS F. Areias 1,2,3 , C. Correia 1 , A. Rocha 1 , J. Brea 2 , M. Castro 2 , M.I. Loza 2 , M.F. Proença 1 , M.A. Carvalho 1 1 . Universidade do Minho, Braga, Portugal; 2 . Universidade de Santiago de Compostela, Santiago de Compostela, Spain; 3 . Yachay Tech University, Urcuquí, Ecuador. In a previous work from our group, in silico target profiling of a chemical library of biologically-orphan molecules led to the identification of novel antagonists for all four members of the adenosine receptor family [1]. Subsequently in silico target profiling of the academic library of 1584 compounds led to the identification of compound 3a containing a purine scaffold as a new hit for the adenosine A 1 receptor (Fig. 1). In order to expand this new chemical series targeting adenosine receptors and to study structure activity relationships, a new series of 24 purines ( 3a-x) were synthesized and their affinities at human adenosine A 1 , A 2A , A 2B and A 3 receptors tested in radioligand binding assays. Adenine derivatives were substituted at three different positions, N 9 , C 6 and C 2 , of the purine nucleus obtaining compounds with different affinity profiles towards the four adenosine receptors. From the synthesized compounds, five showed high affinity and selectivity for A 1 receptors and seven showed high affinity and selectivity for A 3 receptors. Two of the compounds showed high affinities for both A 1 /A 3 receptors. SAR analysis indicate that, in order to generate high potent and selective ligands for A 1 , A 3 and dual A 1 /A 3 receptors, a hydrogen atom must be in N 9 and an aryl group must be in C 2 , while the group in C 6 (piperidinyl vs 4- methylpirazinyl) combined with a specific aryl group in C 6 seems to govern selectivity. Functional studies indicated antagonist activity at A 1 and A 3 receptors for selected compounds of the series. In conclusion, a number of purine-based compounds are described in this study, among them fourteen molecules with marked selectivity and antagonist activity at A 1 , A 3 or dual A 1 /A 3 adenosine receptors at submicromolar concentration. These purine scaffolds constitute an important source for novel biochemical tools and/or therapeutic drugs. Figure 1. Novel purine hit ( 3a ) for adenosine A 1 receptor identified by in silico target profiling. References:[1] F. Areias, J. Brea, E. Gregori-Puigjane, M. Zaki, M.A. Carvalho, E. Dominguez, H. Gutierrez-de-Teran, M. Proença, M. Loza, J. Mestres, Bioorg. Med. Chem. 18 (2010) 3043-3052.