Shine and rise! GABAA–receptors are ligand-gated chloride channels that respond to the major inhibitory neurotransmitter of the mammalian central nervous system. Herein, we introduce azobenzene derivatives of propofol that increase GABA-induced currents when irradiated with light and thus function as photochromic potentiators. One of our molecules, AP2, can be employed as a light-dependent general anesthetic in translucent tadpoles.

Shine and rise! GABA A -receptors are ligand-gated chloride channels that respond to the major inhibitory neurotransmitter of the mammalian central nervous system. Herein, we introduce azobenzene derivatives of propofol that increase GABA-induced currents when irradiated with light and thus function as photochromic potentiators. One of our molecules, AP2, can be employed as a light-dependent general anesthetic in translucent tadpoles. Keywordspropofol; azobenzenes; GABA receptors; photopharmacology GABA A receptors are pentameric ligand-gated ion channels that are activated by the major inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA). [1] Binding of GABA results in the opening of a chloride ion-selective pore, thusCorrespondence to: Erwin Sigel, erwin.sigel@mci.unibe.ch; Dirk Trauner, dirk.trauner@lmu.de. 1 These authors contributed equally to this work.Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. hyperpolarizing the postsynaptic neuron and decreasing the likelihood of action potential firing. As such, GABA A receptors are a prominent target for anesthetic, hypnotic, and anticonvulsant drugs (Fig. 1). [2,3] While agonists, antagonists and blockers of GABA A receptors, such as muscimol, gabazine, or picrotoxinin, respectively, have proven to be valuable research tools, their impact on human medicine has been limited. Drugs that target these receptors are dominated by allosteric modulators that potentiate, i.e. increase, chloride currents elicited by the neurotransmitter. Well-established potentiators include benzodiazepines (e.g. diazepam), barbiturates (e.g. phenobarbital), the imidazopyridine zolpidem and the simple phenol propofol. [2] These bind to distinct allosteric sites on GABA A receptors increasing the mean open time or the opening frequency of the channel. However, the analysis of their exact binding sites at a molecular level has been complicated by a lack of detailed structural data. NIH Public AccessFollowing its discovery in 1980, propofol has become the most widely used intravenous general anaesthetic. [4] Although its mode of action has not been fully elucidated, it is commonly accepted that the anaesthesia induced by this unusually lipophilic drug mostly results from potentitation of GABA-induced currents, as well as a direct activation of the chloride channel at low concentrations. Propofol has a rapid onset and offset of action and shows only minimal accumulation upon prolonged use. The intravenous administration of propofol is also associated with reduced postoperative nausea and vomiting. [5] While GABA A -receptors respond to a variety of ligands, they are normally not sensitive toward light. It would be fascinating to confer light-sensitivity to these ion channels, since light is unsurpassed in terms of the temporal and spatial precision it provides. This could be indirectly achieved via ligands that act on the receptors but can be optically switched between an active and an inacti...

Background We previously developed two etomidate analogs that retain etomidate’s favorable hemodynamic properties, but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl-etomidate (MOC-etomidate) is rapidly metabolized and ultra-short acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11β-hydroxylase. We hypothesized that MOC-etomidate’s labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of methoxycarbonyl-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a “soft” analog of carboetomidate. Methods MOC-carboetomidate’s octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate’s EC50 and ED50 for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on gamma-aminobutyric acid A (GABAA) receptor function was assessed using two-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. Results MOC-carboetomidate’s octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate’s EC50 for LORR in tadpoles was 9 ± 1 µM and its EC50 for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABAA receptor currents by 400 ± 100%. Its metabolic half-life in pooled rat blood was 1.3 minutes. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs. 15 ± 3, respectively; p = 0. 0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. Conclusions MOC-carboetomidate is a GABAA receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.

Background Etomidate is a sedative–hypnotic that is often given as a single intravenous bolus but rarely as an infusion because it suppresses adrenocortical function. Methoxycarbonyl etomidate and (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) are etomidate analogs that do not produce significant adrenocortical suppression when given as a single bolus. However, the effects of continuous infusions on adrenocortical function are unknown. In this study, we compared the effects of continuous infusions of etomidate, methoxycarbonyl etomidate, and carboetomidate on adrenocortical function in a rat model. Methods A closed-loop system using the electroencephalographic burst suppression ratio as the feedback was used to administer continuous infusions of etomidate, methoxycarbonyl etomidate, or carboetomidate to Sprague–Dawley rats. Adrenocortical function was assessed during and after infusion by repetitively administering adrenocorticotropic hormone 1–24 and measuring serum corticosterone concentrations every 30 min. Results The sedative–hypnotic doses required to maintain a 40% burst suppression ratio in the presence of isoflurane, 1%, and the rate of burst suppression ratio recovery on infusion terminationvaried(methoxycarbonyletomidate>carboetomidate > etomidate). Serum corticosterone concentrations were reduced by 85% and 56% during 30-min infusions of etomidate and methoxycarbonyl etomidate, respectively. On infusion termination, serum corticosterone concentrations recovered within 30 min with methoxycarbonyl etomidate but persisted beyond an hour with etomidate. Carboetomidate had no effect on serum corticosterone concentrations during or after continuous infusion. Conclusions Our results suggest that methoxycarbonyl etomidate and carboetomidate may have clinical utility as sedative–hypnotic maintenance agents when hemodynamic stability is desirable.

Background Methoxycarbonyl etomidate is the prototypical ultra-rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clinical uses. We hypothesized that its duration of action could be lengthened and clinical utility broadened by incorporating specific aliphatic groups into the molecule to sterically protect its ester moiety from esterase-catalyzed hydrolysis. To test this hypothesis, we developed a series of methoxycarbonyl etomidate analogs (spacer-linked etomidate esters) containing various aliphatic protecting groups and spacer lengths. Methods Spacer-linked etomidate esters were synthesized and their hypnotic potencies and durations of action following bolus administration were measured in rats using a loss of righting reflexes assay. Octanol:water partition coefficients and metabolic half-lives in pooled rat blood were determined chromatographically. Results All spacer-linked etomidate esters produced hypnosis rapidly and in a dose-dependent manner. ED50s for loss of righting reflexes ranged from 0.69 ± 0.04 mg/kg for cyclopropyl-methoxycarbonyl metomidate to 11.1 ± 0.8 mg/kg for methoxycarbonyl metomidate. The slope of a plot of the duration of loss of righting reflexes versus the logarithm of the dose ranged 12-fold among spacer-linked etomidate esters, implying widely varying brain clearance rates. The in vitro metabolic half-lives of these compounds in rat blood varied by more than two orders of magnitude and were diastereometrically-selective. Conclusions We created 13 new analogs of methoxycarbonyl etomidate and identified two that have significantly higher potency and potentially address methoxycarbonyl etomidate’s too brief duration of action. This work may provide a blueprint for optimizing the pharmacological properties of other soft drugs.