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→Mechanisms of Anesthesia
*Based on 30 years of in vitro studies (n>300), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.
*Based on 30 years of in vitro studies (n>300), most anesthetics exhibit similar potency across a range of receptors. Most receptors are non-selective for ligands. What this paper addresses but doesn't answer is whether the receptors are present at the correct locations and necessary to the anesthetic behavioral response.
*Some anesthetics ('''ketamine, dexmedetomidine, etomidate, benzos''') are fairly selective, but are rarely used as sole anesthetics.
*Some anesthetics ('''ketamine, dexmedetomidine, etomidate, benzos''') are fairly selective, but are rarely used as sole anesthetics.
**Ketamine binds to α4β4 nAChR w/ IC<sub>50</sub> of 0.144 uM, but has an IC<sub>50</sub> for the GluN1/N2C NMDAR of 0.338 uM.
**Dexmedetomidine binds to α<sub>2A</sub> AR w/ K<sub>D</sub> of 0.0014 uM and the M<sub>3</sub> mAChR w/ IC<sub>50</sub> of 0.001 uM.
**Etomidate binds to α1β2γ2 GABA<sub>A</sub>R w/ an EC<sub>50</sub> of 1.08 uM, but to I<sub>K(dr)</sub> with an IC<sub>50</sub> of 4.59 uM, and the α1 GlyR w/ an IC<sub>50</sub> of 5.37 uM.
**Midazolam binds to α1β2γ2 GABA<sub>A</sub>R w/ EC<sub>50</sub> of 0.041 uM, Na<sub>V</sub> (neuron) IC<sub>50</sub> of 0.074 uM, and nAChR (muscle) w/ IC<sub>50</sub> of 0.143 uM.
**Diazepam binds to α1β2γ2 GABA<sub>A</sub>R w/ EC<sub>50</sub> of 0.07 uM.
**Sevoflurane binds to K<sub>v</sub>1.2 w/ EC<sub>50</sub> of 0.0097 mM.
*[https://scholar.googleusercontent.com/scholar.bib?q=info:dK96wvRnWFAJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixESwUs:ACTRDVEAAAAAasUU2UsAEqSgPmvYJRTMHcZKb4s&scisig=ACTRDVEAAAAAasUU2a34RqVYzDaWRdbVsL76Mk4&scisf=4&ct=citation&cd=-1&hl=en 2026 A&A paper] argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABA<sub>A</sub>R receptor.
*[https://scholar.googleusercontent.com/scholar.bib?q=info:dK96wvRnWFAJ:scholar.google.com/&output=citation&scisdr=CiBKb9IEEIjgixESwUs:ACTRDVEAAAAAasUU2UsAEqSgPmvYJRTMHcZKb4s&scisig=ACTRDVEAAAAAasUU2a34RqVYzDaWRdbVsL76Mk4&scisf=4&ct=citation&cd=-1&hl=en 2026 A&A paper] argues that classifying anesthetics as, say, GABAergic vs. NMDAergic is misleading. Propofol for instance actually has higher potency at the α4β2 nAChR and HCN1 receptors than at the "classic" GABA<sub>A</sub>R receptor.
*'''Are there pharmacological inhibitors with receptor specificity? When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA<sub>A</sub>R inhibitor? Could you do optogenetic location-specific inducible receptor knockdowns? Do model organisms already exist?'''
*'''Are there pharmacological inhibitors with receptor specificity? When given together with "promiscuous" anesthetics, what happens? For instance, is propofol equally effective when given with a specific HCN1 receptor inhibitor? What about a GABA<sub>A</sub>R inhibitor? Could you do optogenetic location-specific inducible receptor knockdowns? Do model organisms already exist?'''