Chirality in Anesthesia I: Minimum Alveolar Concentration of Secondary Alcohol Enantiomers

Won, Albert; Oh, Irene; Laster, Michael J.; Popovich, John; Eger, Edmond I.; Sonner, James M.

doi:10.1213/01.ane.0000217199.90426.7d

Cited by 8 publications

(11 citation statements)

References 14 publications

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“…S2 and Chiral Contribution to Phase Separation). Furthermore, different enantiomers of the same anesthetic molecule have been shown to have different potencies (70)(71)(72). Our theory presents a paradigm through which chirality affects physical membrane properties, in accordance with the classic hypothesis that anesthetic molecules disrupt membrane phase behavior (73,74).…”

Section: Discussionsupporting

confidence: 80%

Chiral twist drives raft formation and organization in membranes composed of rod-like particles

Kang

Lubensky

2016

Proc. Natl. Acad. Sci. U.S.A.

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Lipid rafts are hypothesized to facilitate protein interaction, tension regulation, and trafficking in biological membranes, but the mechanisms responsible for their formation and maintenance are not clear. Insights into many other condensed matter phenomena have come from colloidal systems, whose micron-scale particles mimic basic properties of atoms and molecules but permit dynamic visualization with single-particle resolution. Recently, experiments showed that bidisperse mixtures of filamentous viruses can self-assemble into colloidal monolayers with thermodynamically stable rafts exhibiting chiral structure and repulsive interactions. We quantitatively explain these observations by modeling the membrane particles as chiral liquid crystals. Chiral twist promotes the formation of finite-sized rafts and mediates a repulsion that distributes them evenly throughout the membrane. Although this system is composed of filamentous viruses whose aggregation is entropically driven by dextran depletants instead of phospholipids and cholesterol with prominent electrostatic interactions, colloidal and biological membranes share many of the same physical symmetries. Chiral twist can contribute to the behavior of both systems and may account for certain stereospecific effects observed in molecular membranes. membrane rafts | liquid crystals | chirality | self-assembly | colloids F ilamentous viruses have proved to be a fruitful colloidal system (1-19). They serve as monodisperse, rigid, and chiral rods that are ∼1 µm in length and interact effectively through hard-core repulsion (2, 7). When suspended in an aqueous solution at increasing concentrations, they transition from a disordered isotropic phase to a cholesteric (chiral nematic) phase characterized by alignment along a director field that twists with a preferred handedness and wavelength (1, 6). The addition of a nonadsorbing polymer such as dextran induces lateral virusvirus attraction via the depletion interaction (10,12,20,21). The viruses self-assemble into monolayers that exhibit fluid-like dynamics internally (10) and sediment to the bottom of glass containers, which are coated with a polyacrylamide brush to suppress depletion-induced virus-wall attractions (22). The rich physics and phenomenology of membranes formed from singlevirus species have been thoroughly studied (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)19). However, two-species membranes demonstrate a novel set of behaviors that are not adequately understood (18). We review these behaviors now before describing a theory that can explain them.fd-Y21M and M13KO7, which we shorten to fd and M13 for convenience, are two species of filamentous virus that have slightly different lengths and form cholesteric phases of opposite handednesses (Table 1 and Fig. 1A). Membranes composed of both fd and M13 viruses are circular with interior particles aligned largely perpendicularly to the membrane plane and edge particles tilted azimuthally, as in single-species membranes (13). At low dextran concentrations, the two spec...

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Section: Discussionsupporting

confidence: 80%

Chiral twist drives raft formation and organization in membranes composed of rod-like particles

Kang

Lubensky

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Racemic alcohols were prepared from equal parts of each stereoisomer. The applied alcohol concentrations (16 mM 2-butanol; 4 mM 2-pentanol; and 2 mM 2-hexanol) are close to the blood alcohol concentrations measured at MAC in rats (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Alcohol vapor concentrations in equilibrium with perfusate were determined at the end of each experiment using headspace gas chromatography with a Carbowax column (Series 580; Gow-Mac, Bethlehem, PA), from which solution concentrations were calculated using previously determined Ostwald saline-gas partition coefficients at room temperature (11).…”

Section: Methodssupporting

confidence: 69%

“…In a companion paper (2) to the present essay, we report that two experimental volatile anesthetics that are readily available, 2-butanol and 2-pentanol, are enantioselective with respect to the minimum alveolar concentration preventing movement in 50% of individuals (MAC) in rats. The differences in MAC for these compounds are similar to those reported for isoflurane, with a 17% change in MAC for the 2-butanol isomers and a 38% change in MAC for the 2-pentanol isomers, compared with a MAC difference reported as 17% in one study (3) and 53% in another study (4) for the isomers of isoflurane.…”

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confidence: 93%

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Chirality in Anesthesia II: Stereoselective Modulation of Ion Channel Function by Secondary Alcohol Enantiomers

Brosnan

Gong

Cotten

et al. 2006

Anesthesia &Amp; Analgesia

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Chirality has been proposed as a means for distinguishing relevant from irrelevant molecular targets of action, but the sensitivity and specificity of this test is unknown for volatile anesthetics. We applied enantiomers of two chiral anesthetic alcohols (2-butanol and 2-pentanol) that are enantioselective for the minimum alveolar concentration (MAC) preventing movement in 50% of animals and one (2-hexanol) that was not to frog oocytes. Each oocyte expressed one of three anesthetic-sensitive ion channels: a Twik-related-spinal cord K+ (TRESK) channel, a gamma-amino butyric acid type A (GABA(A)) receptor and an N-methyl-d-aspartate (NMDA) receptor. Using voltage-clamp techniques, we found that 2-butanol was not enantioselective for any channel (e.g., 16 mM 2-butanol R(-) and S(-) enantiomers decreased current through an NMDA receptors by 44% +/- 3% [mean +/- se] and 37% +/- 4%, respectively); 2-pentanol was enantioselective for one channel (the GABA(A) receptor, the enantiomers increasing current by 277% +/- 20% and 141% +/- 30%); 2-hexanol was enantioselective for both GABA(A) and NMDA receptors (e.g., decreasing current through the NMDA receptor by 19% +/- 3% and 43% +/- 5%). We calculated the sensitivity and specificity of chirality as a test of anesthetic relevance under two scenarios: 1) all three channels were relevant mediators of MAC and 2) no channel was a mediator of MAC. These sensitivities and specificities were poor because there is no consistent correspondence between receptor and whole animal results. We recommend that enantioselectivity not be used as a test of relevance for inhaled anesthetic targets.

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“…[62] developed a series of secondary alcohols, from 2-butanol till 2-heptanol from commercially available secondary alcohols, and tested their enantioselectivity by recording the minimum alveolar anaesthetic concentration (MAC) for these compounds. They found that the 2-butanol and 2-pentanol isomers were enantioselective, the S isomers having 17–38% higher MAC values than the R isomers.…”

Section: Basic Conceptsmentioning

confidence: 99%

Chirality and anaesthetic drugs: A review and an update

Mitra¹,

Chopra²

2011

Indian J Anaesth

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Many molecules can exist as right-handed and left-handed forms that are non-superimposable mirror images of each other. They are known as enantiomers or substances of opposite shape. Such compounds are also said to be chiral (Greek chiros meaning ‘hand’). Such chiral molecules are of great relevance to anaesthetic theory and practice. This review summarizes the basic concepts, pharmacokinetic and pharmacodynamic aspects of chirality, and some specific examples of their application in anaesthesia, along with recent advances to elucidate the anaesthetic mechanisms. Chirality is relevant to anaesthesia, simply because more than half of the synthetic agents used in anaesthesia practice are chiral drugs. Almost all these synthetic chiral drugs are administered as racemic mixture, rather than as single pure enantiomers. These mixtures are not drug formulations containing two or more therapeutic substances, but combination of isomeric substances, with the therapeutic activity residing mainly in one of the enantiomer. The other enantiomer can have undesirable properties, have different therapeutic activities or be pharmacologically inert. Specific examples of application of chirality in anaesthetic drugs include inhalational general anaesthetics (e.g. isoflurane), intravenous anaesthetics (e.g. etomidate, thiopentone), neuromuscular blocking agents (e.g. cisatracurium), local anaesthetics (e.g. ropivacaine and levobupivacaine) and other agents (e.g. levosimendan, dexmedetomidine, L-cysteine). In the recent advances, chirality study has not only helped new drug development as mentioned above, but has also contributed in a more profound way to the understanding of the mechanism of anaesthesia and anaesthetic drugs.

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Chirality in Anesthesia I: Minimum Alveolar Concentration of Secondary Alcohol Enantiomers

Cited by 8 publications

References 14 publications

Chiral twist drives raft formation and organization in membranes composed of rod-like particles

Chiral twist drives raft formation and organization in membranes composed of rod-like particles

Chirality in Anesthesia II: Stereoselective Modulation of Ion Channel Function by Secondary Alcohol Enantiomers

Chirality and anaesthetic drugs: A review and an update

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