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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_2AAR), seeking new α_2AAR agonists chemotypes that lack the sedation conferred by known α_2AAR 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_2AAR 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 (EC₅₀) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC₅₀ 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 …