The Anaesthetic Action and Modulation of GABA A Receptor Activity by the Novel Water-soluble Aminosteroid Org 20599

Hill-Venning, Claire; Peters, John A.; Callachan, Helen; Lambert, Jeremy J.; Gemmell, David K.; Anderson, Alison; Byford, Alan; Hamilton, Niall M.; Hill, David R.; Marshall, Richard; Campbell, A. C.

doi:10.1016/s0028-3908(96)00069-x

Cited by 33 publications

(19 citation statements)

References 57 publications

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“…Although brain region-dependent variation in binding and function of GABA A receptor has been reported (Lambert et al, 1995;Yamakura et al, 2001), it appears that the biphasic effects of neuroactive steroids are not related to receptor heterogeneity but that in various tissues the efficacy of GABA A receptor modulators varies due to the dual actions that they have on GABA A receptor channels: i.e., the allosteric modulation of GABA binding and direct channel activation at higher concentrations (Srinivasan et al, 1999). It has been shown that neuroactive steroids can produce biphasic responses via single neurons (MacIver and Roth, 1987;Dallwig et al, 1999), (recombinant) receptors (Lambert et al, 1995;Hill Venning et al, 1996), and in hippocampal CA1 pyramidal cell (Burg et al, 1998). This is in agreement with another report that suggested that GABA A receptor response may change from inhibitory to excitatory, depending on the frequency (i.e., intensity) of stimulation (Archer and Roth, 1999).…”

supporting

confidence: 89%

“…The estimated in vivo K PD for alphaxalone of 432 Ϯ 26 ng ⅐ ml Ϫ1 is in the range of values reported for the (indirect) inhibition of 35 S-t-butylbicyclophosphorothionate binding by alphaxalone, for which the IC 50 varied between 110 and 180 ng ⅐ ml Ϫ1 (Hill Venning et al, 1996;Anderson et al, 1997) and values reported for in vitro functional studies with recombinant receptors, for which the EC 50 was ϳ730 ng ⅐ ml Ϫ1 (Hill Venning et al, 1996). Using this mechanism-based PK/PD approach for the determination of the in vivo K PD will allow comparison between biphasic EEG effects of other compounds, but also between these biphasic EEG effects and other pharmacodynamic endpoints in vivo and in vitro studies.…”

supporting

confidence: 53%

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Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Visser

Smulders²,

Reijers³

et al. 2002

J Pharmacol Exp Ther

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The neuroactive steroid alphaxalone reveals a complex biphasic concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The proposed model is based on receptor theory and aims to separate the drug-receptor interaction from the transduction of the initial stimulus into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered intravenously in various dosages. The pharmacokinetics were described by a two-compartment model, and parameter estimates for clearance, intercompartmental clearance, volume of distribution 1 and 2 were 158 Ϯ 29 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 143 Ϯ 31 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 122 Ϯ 20 ml ⅐ kg Ϫ1 and 606 Ϯ 48 ml ⅐ kg Ϫ1 , respectively. Concentration-effect relationships exhibited a biphasic pattern and delay in onset of effect. The hysteresis was described on the basis of an effect-compartment model with C max as covariate. The pharmacodynamic model consisted of a receptor model, featuring a monophasic saturable receptor activation model in combination with a biphasic stimulus-response model. The in vivo affinity (K PD ) was estimated at 432 Ϯ 26 ng ⅐ ml Ϫ1 . Unique parameter estimates were obtained that were independent of the dose and the duration of the infusion. In conclusion, we have shown that this mechanism-based approach, which separates drug-and system-related properties in vivo, was successfully applied for the characterization of the biphasic effect versus time patterns of alphaxalone. The model should be of use in the characterization of other biphasic responses.The sedative-hypnotic and anesthetic properties of a wide range of natural and synthetic steroids were first shown by Selye (1942). This initial work led to the introduction of the synthetic neuroactive steroid alphaxalone (5␣-pregnan-3␣-ol-11,20-dione) into clinical medicine (Sear, 1996). Alphaxalone exerts its selective action via a specific binding site at the GABA A receptor complex and does not interact with any of the classical cytosolic hormonal steroid receptors (Paul and Purdy, 1992;Lambert et al., 1995). Detailed mechanistic investigations have revealed a dual mechanism of action for alphaxalone. Low concentrations of alphaxalone allosterically modulate the amplitude of GABA-induced ion currents, whereas alphaxalone at higher concentrations (Ն1 M) acts as an agonist, similar to that observed by barbiturates (Cottrell et al., 1987;Paul and Purdy, 1992;Lambert et al., 1995). Recently, there has been a renewed interest in neuroactive steroids in relation to the development of novel strategies for the treatment of anxiety, insomnia, migraine, depression, and seizure disorders (Gasior et al., 1999). However, very few attempts have been made to study neuroactive steroids in vivo on the basi...

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supporting

confidence: 89%

supporting

confidence: 53%

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Visser

Smulders²,

Reijers³

et al. 2002

J Pharmacol Exp Ther

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“…The morpholinyl conjugation in the A-ring served to facilitate the hydrogen bonding of the 3a group rather than steric hindrance of binding. However, ORG-20599 possessed very weak potency in 6-Hz antiseizure function in vivo that could be related to pharmacokinetic dissimilarity compared with previous reports of comparable potency to 3a5a-AP at anesthetic doses (Hill-Venning et al, 1996).…”

Section: Discussionmentioning

confidence: 54%

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Carver

Reddy

2016

Journal of Pharmacology and Experimental Therapeutics

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Synaptic GABA A receptors are primary mediators of rapid inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurologic disorders. The d-subunit GABA A receptors are expressed extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. However, the neurosteroid structure-function relationship at dGABA A receptors within the native hippocampus neurons remains unclear. Here we report a structure-activity relationship for neurosteroid modulation of extrasynaptic GABA A receptor-mediated tonic inhibition in the murine dentate gyrus granule cells. We recorded neurosteroid allosteric potentiation of GABA as well as direct activation of tonic currents using a wide array of natural and synthetic neurosteroids. Our results shows that, for all neurosteroids, the C3a-OH group remains obligatory for extrasynaptic receptor functional activity, as C3b-OH epimers were inactive in activating tonic currents. Allopregnanolone and related pregnane analogs exhibited the highest potency and maximal efficacy in promoting tonic currents. Alterations at the C17 or C20 region of the neurosteroid molecule drastically altered the transduction kinetics of tonic current activation. The androstane analogs had the weakest modulatory response among the analogs tested. Neurosteroid potentiation of tonic currents was completely (approximately 95%) diminished in granule cells from d-knockout mice, suggesting that d-subunit receptors are essential for neurosteroid activity. The neurosteroid sensitivity of dGABA A receptors was confirmed at the systems level using a 6-Hz seizure test. A consensus neurosteroid pharmacophore model at extrasynaptic dGABA A receptors is proposed based on a structure-activity relationship for activation of tonic current and seizure protection.

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“…This is in agreement with the observations that all these neuroactive steroids were able to induce anesthesia in a similar way. Furthermore, in in vitro investigations on the modulation of human recombinant GABA A receptors in oocytes, ORG 20599, and alphaxalone differed only little in the maximal enhancement and potency (Hill-Venning et al, 1996). It seems reasonable to assume that the efficacy of neuroactive steroids cannot be higher in vivo, because the isoelectric EEG at higher dosages indicates that the physiological limit has been reached.…”

Section: Discussionmentioning

confidence: 96%

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Visser¹,

Gladdines²,

Graaf³

et al. 2002

J Pharmacol Exp Ther

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The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2␤-3␣-5␣-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2␤-3␣-5␣-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation (e PD ) were similar for the different neuroactive steroids but values of the potency estimate (K PD ) ranged from 157 Ϯ 16 ng ⅐ ml Ϫ1 for pregnanolone, 221 Ϯ 83 ng ⅐ ml Ϫ1 for ORG 20599, and 483 Ϯ 42 ng ⅐ ml Ϫ1 for alphaxalone to 1619 Ϯ 208 ng ⅐ ml Ϫ1 for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC 50 in an in vitro [ 35 S]t-butylbicyclophosphorothionate binding assay (r ϭ 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA A receptor in vivo.

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The Anaesthetic Action and Modulation of GABA A Receptor Activity by the Novel Water-soluble Aminosteroid Org 20599

Cited by 33 publications

References 57 publications

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

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The Anaesthetic Action and Modulation of GABA A Receptor Activity by the Novel Water-soluble Aminosteroid Org 20599

Cited by 33 publications

References 57 publications

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABAAReceptor in Vivo

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Product

Resources

About

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo