General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctive agents for surgical procedures. Nevertheless, they have potential adverse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in vulnerable populations such as the very young and the frail elderly. It would be desirable therefore to have alternative agents that are just as efficacious, but have a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core ( viz., an N-arylpyrrole derivative) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pave the way for new general anesthetics that are safer and easier to use.
General anesthetics possess characteristics that make them valuable for use during a wide variety of surgical procedures [
General anesthetics share common biological effects, but consist of a perplexing array of differing chemical structures (
The currently-used general anesthetics generally do not have exclusive activity at only GABAA receptors. They also have activity at other receptor sites as well [
The GABAA receptor is a member of the ligand-gated ion channel (LGIC) Cys-loop class of receptors. Five subunits (γ-α-β-α-β linkage) form a central ion (Cl–)-conducting pore. General anesthetics potentiate the action of GABA (transmembrane Cl– influx), resulting in hyperpolarization and inhibitory actions on neurons [
General anesthetics are believed to bind to the transmembrane region of the GABAAR, and interaction with specific amino acid residues is believed to be
essential for anesthetic action [
Anesthetic | GABAA | Glycine | AMPA/Kainate | NMDA (+Gly) | Nicotinic-ACh | 5-HT3 |
---|---|---|---|---|---|---|
Alphaxalone | | ¯¯ | ||||
Etomidate | | |||||
Pentobarbital | | ¯¯ | ¯ | ¯¯¯ | ¯ | |
Propofol | | | ¯¯ | ¯ |
likelihood to fire (action potential) in response to excess presynaptic activity. This is mirrored at the organism level in an anesthetic action [
Isolation and purification of LGIC receptors such as the GABAAR is technically difficult, and there were no high-resolution crystal structures of the open-state of the GABAAR, the conformation to which general anesthetics are thought to interact and stabilize [
The amino acid sequences for the human GABAAR (hGABAAR) were obtained from the National Center for Biotechnology Information (NCBI). Then, in short, homologous template receptors were identified from imported GABAAR subunit sequences based on their sequence similarity. The sequence for each hGABAAR subunit was then aligned to the corresponding subunit of the template, arranged for modeling, and connected in order to create a 3-dimensional model of a complete heteropentameric hGABAAR. The resultant homology model is shown in
The energetically minimized, optimized homology model of the hGABAAR (as described above) was used to model the transmembrane intersubunit space that is thought to be the binding site for general anesthetics [
Using the above model of the binding pocket for general anesthetics on the human GABAA receptor, Cayla et al. (2019) used high-throughput in silico screening
to identify candidate compounds that exhibited goodness of fit to the modelled binding pocket, and thus were potential mimetics of current general anesthetics with potential anesthetic action of their own [
In addition to the hGABAAR docking procedure used to model efficacy, it was desired to also address the AE issues associated with general anesthetics. Toward this end, previous findings related to the known unwanted interaction of etomidine with the enzyme thought to be related to the AE of adrenal suppression, 11-β-hydroxylase [
The in vitro testing revealed:
• BB, similar to etomidate, acts specifically through GABAAR-slow receptors (propofol has additional effects on GABAAR-fast and tonic receptors) [
• The effect was fully reversed by the GABAAR-selective Cl– ion channel blocker picrotoxin.
• BB slowed decay of electrically-evoked IPSCs (inhibitory postsynaptic currents) in whole-cell voltage-clamp recordings from CA1 pyramidal cells in mice.
• BB dose-dependently potentiated GABA-induced currents on GABAA receptors expressed in Xenopus oocytes.
The potential anesthetic activity of BB was tested in vivo using the standard methods
of measuring the loss-of-righting reflex (LORR) in tadploes and rats [
Likewise, intravenous injection of BB to rats produced a reversible loss of righting-reflex, without signs of abnormal behavior or toxicity.
The hemodynamic profile of compound BB was tested in rats and compared to propofol.The intravenous injection of propofol at a typical anesthetic-induction dose produced a significant decrease in both systolic and diastolic arterial blood pressure. In contrast, at a dose more than 4-fold that required producing LORR, BB did not alter either systolic or diastolic arterial blood pressure [
Etomidate interacts with the heme iron in 11-β-hydroxylase and, as a result, causes an almost complete suppression of the synthesis of corticosterone [
Compound BB recently reported by Cayla et al. (2019) might provide the anesthetic efficacy of currently-used general anesthetic drugs, but with a better safety profile. However, even in the absence of future clinical utility, the approach (in silico modeling and compound screening coupled with in vivo efficacy and adverse-effect testing) provides an elegant demonstration of the power of computer-modeling techniques toward drug discovery.
The authors declare no conflicts of interest regarding the publication of this paper.
Raffa, R.B., Pergolizzi Jr., J.V. and Taylor Jr., R. (2019) Designing General Anesthetics That Have a Better Safety Profile. Pharmacology & Pharmacy, 10, 407-415. https://doi.org/10.4236/pp.2019.1010033