Non-opioid, non-sedating analgesic targeting ADRA2A

A small molecule agonist of the GPCR adrenergic receptor ADRA2A that lacks the sedative effects of marketed ADRA2A agonists could help treat pain.

An in silico screen of over 300 million compounds for docking to ADRA2B — which is similar to ADRA2A and has an available structure — followed by selection, synthesis and in vitro testing of hits whose structures differ from those of marketed ADRA2A agonists identified a pyridyl-isoquinolyl that activated ADRA2A with an EC50 of 52 nM, with a strong bias for signaling via the Gi protein family instead of via β-arrestin; subsequent optimization yielded a lead compound with an EC50 of 4.8 nM...