Designing General Anesthetics That Have a Better Safety Profile

General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are rou-tinely 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 produc-tion), 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.

. These AEs are usually adequately avoided or handled by the anesthesiologist, but vulnerable populations, such as the very young or the frail elderly, are more at-risk [5] [6] [7] [8].
General anesthetics share common biological effects, but consist of a perplexing array of differing chemical structures ( Figure 1). The group includes molecules as small as the single atom xenon, and as large as the 56-atom alfaxalone [9] [10] [11]. Such chemical diversity impeded the discovery of a common mechanism of action. Many theories have been proposed [12]. It is now accepted that most of the commonly-used general anesthetics act by an action on a specific sub-region of the large γ-aminobutyric acid type A receptor (GABA A R) complex ( Figure 2)

The GABAAR and General Anesthetic Action
The General anesthetics are believed to bind to the transmembrane region of the GABA A R, and interaction with specific amino acid residues is believed to be

Modeling the General Anesthetic Binding Pocket
The energetically minimized, optimized homology model of the hGABA A R (as described above) was used to model the transmembrane intersubunit space that is thought to be the binding site for general anesthetics [30]. Three amino acid residues that were previously shown to be essential for anesthetic activity (β 3 -N265, β 3 -M286, α 1 -L232) were mapped to form a putative anesthetic binding pocket. A molecule of propofol was manually docked in this binding pocket in an orientation to mimic pharmacologic relevance (e.g. minimizing steric hindrance) and an energetically-optimized binding cavity was obtained. A series of propofol derivatives were fit to the model and used to test model reliability by comparing calculated binding affinities with known values.

Identification of Novel Anesthetic Compounds
Using  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 [26].
In addition to the hGABA A R 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 [35] [36], were incorporated, resulting in a unique molecular core in silico [37] [38] [39] [40]. High-throughput structural screening identified 11 compounds that have 'fits' compatible with the critical binding core.
The most potent of the 11 compounds, an N-arylpyrrole derivative ( Figure 5), termed "BB", was tested in vitro and in vivo for anesthetic activity and AE potential.
The in vitro testing revealed:  BB, similar to etomidate, acts specifically through GABA A R-slow receptors (propofol has additional effects on GABA A R-fast and tonic receptors) [41] [42].  The effect was fully reversed by the GABA A R-selective Clion 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 GABA A receptors expressed in Xenopus oocytes.

In Vivo Evaluation of Potential Anesthetic Activity
The potential anesthetic activity of BB was tested in vivo using the standard methods  . Chemical structure of lead compound "BB" [26].
of measuring the loss-of-righting reflex (LORR) in tadploes and rats [43] [44]. BB produced dose-related LORR in tadpoles, which was reversed when the animals were subsequently placed into a drug-free water bath. Likewise, intravenous injection of BB to rats produced a reversible loss of righting-reflex, without signs of abnormal behavior or toxicity.

In Vivo Evaluation of Potential AE Activity
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 [26].
Etomidate interacts with the heme iron in 11-β-hydroxylase and, as a result, causes an almost complete suppression of the synthesis of corticosterone [45]. In contrast, in the same procedure, compound BB did not alter baseline of ACTHstimulated corticosterone levels in rats [26].

Conclusion
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.