The adenosine neuromodulation system (A1R and A2AR) has been identified as a key target for the management of neurodegenerative diseases, and recent findings suggest that PDE10A also plays a role in Parkinson’s, Huntingdon’s disease, and schizophrenia. Therefore, there is therapeutic potential for multi-target ligands against A1R, A2AR and PDE10A in neurodegenerative diseases. We describe here the design of A1R/A2AR/PDE10A multi-target ligands following a retrosynthetic approach employing in silico target prediction and docking. As a result, triazoloquinazolines were predicted to show activity at A1R, A2AR and PDE10A, and were validated experimentally as A1R/A2AR-PDE10A multi-target ligands. Six known PDE 10A inhibitors were initially evaluated pharmacologically using yeast screening platform, as well as CHO-K1 cells expressing the adenosine receptors. This identified them as A1R/A2AR-PDE10A multi-target ligands, among which three are selective A2AR agonists elevating cellular cAMP levels with measured pEC50 values of 7.6 ±0.2, 7.2 ±0.4, and 6.4 ±0.5 (n=5), and mediating ERK1/2 activation in an A2AR dependent manner. Hence, we have discovered triazoloquinazolines as a new generation of A1R/A2AR/PDE10A multi-target ligands, and we are currently validating the synergistic effect that these multi-target ligands exhibit in elevating cAMP levels in the ST14A cells. Moreover, our computational approach may be generally applicable to a wide range of multi-target ligand design problems.

Rational design and evaluation of multi-target ligands at A1R, A2AR and PDE10A with therapeutic potential for neurodegenerative diseases

254th National Meeting (2017)

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