Discovery of a peripherally restricted α_2AAR agonist as a safe and broad-spectrum oral analgesic

The development of safe, non-opioid analgesics remains a pressing challenge. The α_2A-adrenergic receptor (α_2AAR) is a valid analgesic target, yet clinical translation has been hindered by dose-limiting central side effects. We discover CC10137, an orally bioavailable, peripherally restricted α_2AAR agonist that produces a robust, dose-dependent anti-allodynic effect across eight murine pain models, without causing sedation, hypotension, or hypothermia. Co-administration of CC10137 (1 mg/kg, p.o.) and morphine (1 mg/kg s.c.) robustly reverses allodynia by 86% in a neuropathic pain model, surpassing either drug alone (∼45%) or a 3-fold higher morphine dose (3 mg/kg, s.c., 65%). This synergy is further replicated in a cancer pain model. Unlike morphine, CC10137 does not impair spinal nociceptive reflex in a tail-flick model, preserving an essential protective mechanism. CC10137 can thus selectively suppress allodynia under a broad spectrum of pathological pain conditions with a favorable safety profile, highlighting its potential as a standalone or combination therapeutic for chronic pain.