Classics in Chemical Neuroscience: Medetomidine

Abstract

Medetomidine is an FDA-approved α₂-adrenoreceptor (α₂-AR) agonist used as a veterinary sedative due to its analgesic, sedative, and anxiolytic properties. While it is marketed for veterinary use as a racemic mixture under the brand name Domitor, the pharmacologically active enantiomer, dexmedetomidine, is approved for sedation and analgesia in the hospital setting. Medetomidine has recently been detected in the illicit drug supply alongside fentanyl, xylazine, cocaine, and heroin, producing pronounced sedative effects that are not reversed by naloxone. The pharmacological effects along with the low cost of supply and lack of regulation for medetomidine has made it a target for misuse. Since 2022, medetomidine has been found as an adulterant in samples of seized drugs, as well as in toxicological analyses of patients admitted to the emergency department after suspected overdoses across several U.S. states and Canada. This Review will discuss the history, chemistry, structure-activity relationships, drug metabolism and pharmacokinetics (DMPK), pharmacology, and emergence of medetomidine as an adulterant in drug mixtures in the context of the current opioid drug crisis.

Keywords: Dexmedetomidine; Fentanyl; Medetomidine; Opioid; Veterinary Medicine; α2-Adrenoreceptors.

Figure 1

Chemical structures of selected α₂-AR agonists.

Scheme 1. First Synthesis of Medetomidine Hydrochloride

Scheme 2. Selected Synthetic Routes for Medetomidine Hydrochloride

Scheme 3. Early-Stage Chiral Resolution of a Key Intermediate for the Synthesis of Dexmedetomidine with the Capability to Recycle the Undesired Enantiomer,

(+)-ADPE = (1S,2R)-(+)-2-amino-1,2-diphenylethanol.

Figure 2

SAR summary of medetomidine.

Figure 3

Crystal structure of dexmedetomidine bound to the α_2A-adrenergic receptor signaling complex (PDB ID: 7EJA). Created using Chimera.

Figure 4

Timeline of the development and recreational use of medetomidine.