Azi-medetomidine: Synthesis and Characterization of a Novel α2 Adrenergic Photoaffinity Ligand

Agonists at the α₂ adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of α₂ adrenergic agonists have the potential both to capture discrete moments of ligand–receptor interactions and to prolong naturalistic drug effects in discrete regions of tissue in vivo. We present here the synthesis and characterization of a novel α₂ adrenergic agonist photolabel based on the imidazole medetomidine called azi-medetomidine. Azi-medetomidine shares protein association characteristics with its parent compound in experimental model systems and by molecular dynamics simulation of interactions with the α_2A adrenergic receptor. Azi-medetomidine acts as an agonist at α_2A adrenergic receptors, and produces hypnosis in Xenopus laevis tadpoles. Azi-medetomidine competes with the α₂ agonist clonidine at α_2A adrenergic receptors, which is potentiated by photolabeling, and azi-medetomidine labels moieties on the α_2A adrenergic receptor as determined by mass spectrometry in a manner consistent with a simulated model. This novel α₂ adrenergic agonist photolabel can serve as a powerful tool for in vitro and in vivo investigations of adrenergic signaling.