Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α _2A -adrenergic receptor (α _2A AR), seeking new α _2A AR agonists chemotypes that lack the sedation conferred by known α _2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G _i and G _o signaling. Experimental structures of α _2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit ‘9087 [mean effective concentration (EC ₅₀ ) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC ₅₀ 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.