m-Azipropofol (AziPm) a Photoactive Analogue of the Intravenous General Anesthetic Propofol

Abstract

Propofol is the most commonly used sedative-hypnotic drug for noxious procedures, yet the molecular targets underlying either its beneficial or toxic effects remain uncertain. In order to determine targets and thereby mechanisms of propofol, we have synthesized a photoactivateable analogue by substituting an alkyldiazirinyl moiety for one of the isopropyl arms but in the meta position. m-Azipropofol retains the physical, biochemical, GABAA receptor modulatory, and in vivo activity of propofol and photoadducts to amino acid residues in known propofol binding sites in natural proteins. Using either mass spectrometry or radiolabeling, this reagent may be used to reveal sites and targets that underlie the mechanism of both the desirable and undesirable actions of this important clinical compound.

Identification of Propofol Binding Sites in a Nicotinic Acetylcholine Receptor with a Photoreactive Propofol Analog*

“…In this study, we used 2-isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol (AziPm), a recently developed photoreactive propofol analog (18), to identify propofol binding sites in the Torpedo nAChR. AziPm acts as a tadpole anesthetic similar in potency to propofol, and it potentiates GABA A R responses at anesthetic concentrations (18).…”

“…AziPm acts as a tadpole anesthetic similar in potency to propofol, and it potentiates GABA A R responses at anesthetic concentrations (18). Although AziPm is related structurally to propofol (see Fig.…”

In Vivo Activation of Azipropofol Prolongs Anesthesia and Reveals Synaptic Targets

“…Photoactive analogs of clinically used general anesthetics have been developed to aid molecular studies (1)(2)(3)(4)(5). These probes share physicochemical properties with their parent molecules, retain anesthetic activity, and undergo photolysis under long wave ultraviolet light (UVA) (315-400 nm), a feature that limits damage to cellular macromolecules upon irradiation following equilibration with the ligands.…”

“…AziPm is an analog of propofol (2,6-diisopropylphenol) that contains an alkyl diazirinyl group in the meta position of the phenol ring (see Fig. 1) (4). In vivo photolabeling of Xenopus laevis tadpoles equilibrated with AziPm results in a previously unreported behavioral phenotype that we call "optoanesthesia."…”

Propofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric Site

“…To assist in the identification of propofol targets and binding sites, photoactive analogs that retain anesthetic efficacy have been developed by our group and others (7)(8)(9)(10). These photolabels can be used to discover novel propofol targets from complex protein mixtures (11)(12)(13).…”