Identification of novel adenosine receptor ((A2BR) antagonosts as antinociceptive and anti-inflammatory agents: 3D QSAR and neuropharmacology studies | Poster Board #2671

Adenisine is known to be an important modulator of inflammation as it exhibit pro-inflammatory and anti-inflammatory response depending on the conditions, ell type and different subtype of adenosine receptors. It is known that adenosine receptor A2BR is upregulated in inflammatory conditions including the glial cells in brain. As selective A2BR antagonists are known to be antinociceptice, we attempted to model about 265 known antagonists from literature using pharmacophore modeling and 3D QSAR. A five point pharmacophore model with two hydrogen bond acceptors (A), two ring aromatics (R) and one hydrogen bond donor (D) was developed. This validated 3DQSAR model was utilized to identify diverse scaffolds against A_2B from our in-house database based on the fitness and predicted activity of the top 15 hits.The hit compounds were explored for adenosine receptor inhibition using a standard cAMP estimation in human prostate cancer cells (PC3 and DU-145) that overexpressed the adenosine receptors. The cell based assay was followed by neuropharmacological screening in animal model of acute and inflammatory models of nociception. Out of the four lead compounds (RS-4, RS-6, RS-9 and RS-12), RS-9 was equipotent as Indomethacin in all the acute pain and carragenan-induced inflammatory models in animals.Further, we measured the levels of tumour necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and nuclear factor (NFκB) in the edema paw tissue using real-time quantitative RT-PCR analysis. Among the tested compounds RS-9 was found to diminish the levels of inflammatory mediators like TNF-α, IL-6 and NFκB but not IL-1β level suggesting its underlying mechanism of anti-inflammatory action.