The Interaction of Intravenous Anesthetic Agents with Native and Recombinant GABAA Receptors

Lambert, Jeremy J.; Belelli, Delia; Pistis, Marco; Hill-Venning, Claire; Peters, John A.

doi:10.1007/978-1-4757-2597-1_5

Cited by 12 publications

(18 citation statements)

References 97 publications

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“…The majority of receptor subtypes found in most regions of the rat brain possess an α 1 subunit (Mohler et al ., 1992). The α 1 β 2 γ 2 receptor complex is also considered a dominant human receptor subunit combination in vivo (Lambert et al ., 1997). Barbiturates primarily exert their sedative and anaesthetic effects by potentiation of the GABA response at GABA A receptors (Huang & Barker 1980; Leeb‐Lundberg & Olsen 1982; Akaike et al ., 1985; 1987; Peters et al ., 1988; Thompson et al ., 1996; ffrench‐Mullen et al ., 1993).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

Cordato

Chebib

Mather

et al. 1999

British J Pharmacology

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1 As pharmacokinetic di erences between the thiopentone enantiomers seem insu cient to explain the *2 fold greater potency for CNS e ects of (7)-S-over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABA A receptor, the primary receptor for barbiturate hypnotic e ects. 2 Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABA A receptor subtype a 1 b 2 g 2 to determine relative di erences in potentiation of the GABA response by rac-, (+)-R-and (7)-S-thiopentone, and rac-pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. 3 With 3 mM GABA, the EC 50 values were (7)-S-thiopentone (mean 26.0+s.e.mean 3.2 mM, n=9 cells) 4rac-thiopentone (35.9+4.2 mM, n=6, P=0.1) 4(+)-R-thiopentone (52.5+5.0 mM, n=8, P50.02) 4rac-pentobarbitone (97.0+11.2 mM, n=11, P50.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC 50 values for (+)-R-or (7)-S-thiopentone. 4 Uninjected oocytes responded to 4100 mM (7)-S-and R-thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2-bis(2-aminophenoxy)ethane-N,N,N1,N1-tetraacetic acid (BAPTA), a Ca 2+ chelating agent. With BAPTA, the EC 50 values were (7)-S-thiopentone (20.6+3.2 mM, n=8) 5(+)-R-thiopentone (36.2+3.2 mM, n=9, P50.005). 5 (7)-S-thiopentone was found to be *2 fold more potent than (+)-R-thiopentone in the potentiation of GABA at GABA A receptors expressed on Xenopus oocytes. This is consistent with the di erences in potency for CNS depressant e ects found in vivo.

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Section: Introductionmentioning

confidence: 99%

Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

Cordato

Chebib

Mather

et al. 1999

British J Pharmacology

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“…Neurotransmittergated ion channels are particularly sensitive to anesthetic agents (2), and within this superfamily a strong case can be made for the involvement of the inhibitory ␥-aminobutyric acid type A (GABA A ) receptor in the action of structurally diverse general anesthetics (2,(7)(8)(9). At anesthetic or subanesthetic concentrations, many general anesthetics act to potentiate GABA A receptor-mediated electrical responses.…”

mentioning

confidence: 99%

“…At anesthetic or subanesthetic concentrations, many general anesthetics act to potentiate GABA A receptor-mediated electrical responses. Higher concentrations of such agents can elicit direct activation of the receptor complex (2,(7)(8)(9).…”

mentioning

confidence: 99%

The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid

Belelli

Lambert

Peters

et al. 1997

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

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359

318

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The ␥-aminobutyric acid type A (GABA A ) receptor is a transmitter-gated ion channel mediating the majority of fast inhibitory synaptic transmission within the brain. The receptor is a pentameric assembly of subunits drawn from multiple classes (␣ 1-6 , ␤ 1-3 , ␥ 1-3 , ␦ 1 , and 1 ). Positive allosteric modulation of GABA A receptor activity by general anesthetics represents one logical mechanism for central nervous system depression. The ability of the intravenous general anesthetic etomidate to modulate and activate GABA A receptors is uniquely dependent upon the ␤ subunit subtype present within the receptor. Receptors containing ␤ 2 -or ␤ 3 -, but not ␤ 1 subunits, are highly sensitive to the agent. Here, chimeric ␤ 1 ͞␤ 2 subunits coexpressed in Xenopus laevis oocytes with human ␣ 6 and ␥ 2 subunits identified a region distal to the extracellular N-terminal domain as a determinant of the selectivity of etomidate. The mutation of an amino acid (Asn-289) present within the channel domain of the ␤ 3 subunit to Ser (the homologous residue in ␤ 1 ), strongly suppressed the GABA-modulatory and GABA-mimetic effects of etomidate. The replacement of the ␤ 1 subunit Ser-290 by Asn produced the converse effect. When applied intracellularly to mouse L(tk؊) cells stably expressing the ␣ 6 ␤ 3 ␥ 2 subunit combination, etomidate was inert. Hence, the effects of a clinically utilized general anesthetic upon a physiologically relevant target protein are dramatically influenced by a single amino acid. Together with the lack of effect of intracellular etomidate, the data argue against a unitary, lipid-based theory of anesthesia.

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“…1,2,15 Clinically, dose titration of propofol is common, particularly upon prolonged infusion, to ensure acceptable emergence from sedation or hypnosis. AZD-3043 is a novel sedative/hypnotic agent, that was designed to be rapidly hydrolyzed by esterases in liver or blood.…”

Section: Discussionmentioning

confidence: 99%

“…1 Acting at a binding site distinct from that of the barbiturates, benzodiazepines or neurosteroid sedative/hypnotics, propofol increases the open probability of GABA A receptor chloride channels. 2 Propofol has gained considerable use for the induction and maintenance of sedation/hypnosis as patient awakening is relatively rapid. However, the rapidity of emergence from propofol-mediated sedation/hypnosis is dose-dependent.…”

Section: Introductionmentioning

confidence: 99%

Azd-3043

et al. 2012

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Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acidA (GABAA) receptor containing a metabolically-labile ester moiety. We postulated that its metabolic pathway would result in a short acting clinical profile. Methods The effects of AZD-3043, propofol and propanidid were studied on GABAA receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous (IV) administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared to propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABAA receptor in vitro and a sedative/hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative/hypnotic agent with rapid and predictable recovery.

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The Interaction of Intravenous Anesthetic Agents with Native and Recombinant GABAA Receptors

Cited by 12 publications

References 97 publications

Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid

Azd-3043

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The Interaction of Intravenous Anesthetic Agents with Native and Recombinant GABAA Receptors

Cited by 12 publications

References 97 publications

Stereoselective interaction of thiopentone enantiomers with the GABAA receptor

Stereoselective interaction of thiopentone enantiomers with the GABAA receptor

The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid

Azd-3043

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Product

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Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor