Xylazine's κ opioid agonist activity is not shared with other FDA-approved α₂-adrenergic agonists

Xylazine is a α₂-adrenergic agonist typically used in as a sedative and analgesic in veterinary medicine. For some years, xylazine has been reported as an additive to fentanyl on the illicit drug market and has been associated with severe side-effects including severe ulcerations and potential amputations at the sites of injection along with an increased risk of respiratory depression and death. We recently reported that xylazine has modest κ opioid agonist activity in vitro and in vivo and asked if other α₂-adrenergic agonists had similar off-target activities. To test this hypothesis, we profiled US FDA-approved α₂-adrenergic agonists at 320 G protein coupled receptors (GPCRs) to identify potentially deleterious and/or beneficial off-targets. Although all other tested α₂-adrenergic agonists were devoid of κ opioid agonist activity, each had a distinct pattern of activity at various GPCRs and differential patterns of signaling bias at α_2-receptor subtypes. These findings suggest potential molecular targets for both side-effects and therapeutic activities among known α₂-adrenergic agonists.