Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases

Table 1 Percent inhibition of the synthesized 4,6-substituted 2-amino-pyridin-3-carbonitriles at 10 µM (PDE10A) or IC₅₀ (µM) and percentage displacement at 0.1 µM (A₁R and A_2AR), or K_i

IC₅₀ values of the 2-aminopyridines-3-carbonitriles were measured for the four phosphodiesterases PDE7A, PDE7B, PDE9A and PDE10A at 10 μM concentration. For those compounds that showed percentage inhibition greater than 70% and selectivity against other measured isoenzymes, IC₅₀ were determined. Calculation of the K_i values at A₁R, A_2AR, A_2BR and A₃R was approximated using the Cheng-Prusoff equation: K_i = IC₅₀/[1 + (C/K_D)], where IC₅₀ is the concentration of compound that displaces the binding of the radioligand by 50%, C is the concentration of radioligand, and K_D is the dissociation constant of each radioligand

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