Gabaergic Pharmacological Activity of Propofol Related Compounds as Possible Enhancers of General Anesthetics and Interaction with Membranes

Abstract

Phenol compounds, such as propofol and thymol, have been shown to act on the GABAA receptor through interaction with specific sites of this receptor. In addition, considering the high lipophilicity of phenols, it is possible that their pharmacological activity may also be the result of the interaction of phenol molecules with the surrounding lipid molecules, modulating the supramolecular organization of the receptor environment. Thus, in the present study, we study the pharmacological activity of some propofol- and thymol-related phenols on the native GABAA receptor using primary cultures of cortical neurons and investigate the effects of these compounds on the micro viscosity of artificial membranes by means of fluorescence anisotropy. The phenol compounds analyzed in this article are carvacrol, chlorothymol, and eugenol. All compounds were able to enhance the binding of [(3)H]flunitrazepam with EC50 values in the micromolar range and to increase the GABA-evoked Cl(-) influx in a concentration-dependent manner, both effects being inhibited by the competitive GABAA antagonist bicuculline. These results strongly suggest that the phenols studied are positive allosteric modulators of this receptor. Chlorothymol showed a bell-type effect, reducing its positive effect at concentrations >100 μM. The concentrations necessary to induce positive allosteric modulation of GABAA receptor were not cytotoxic. Although all compounds were able to decrease the micro viscosity of artificial membranes, chlorothymol displayed a larger effect which could explain its effects on [(3)H]flunitrazepam binding and on cell viability at high concentrations. Finally, it is suggested that these compounds may exert depressant activity on the central nervous system and potentiate the effects of general anesthetics.

Carvacrol presynaptically enhances spontaneous excitatory transmission and produces outward current in adult rat spinal substantia gelatinosa neurons

“…The two actions of carvacrol were concentration-dependent; EC 50 values for the sEPSC frequency increase and outward current were 0.69 mM and 0.55 mM, respectively. These values were similar to EC 50 value (0.419 mM) for the inhibition of AChE by carvacrol (Jukic et al, 2007) while being somewhat larger than that for carvacrol to inhibit compound action potentials in the frog sciatic nerve (0.34 mM; Kawasaki et al, 2013) [ 3 H]flunitrazepam (a benzodiazepine) binding (i.e., to potentiate GABA A -receptor responses) in cultured mouse cortical neurons (0.235 mM; Reiner et al, 2013). Although the two carvacrol actions in SG neurons had comparable EC 50 values, they appeared to be different in origin, because they occurred in a manner independent of each other in that some neurons produced either outward current (Fig.…”

Activation of Human 5-Hydroxytryptamine Type 3 Receptors via an Allosteric Transmembrane Site

“…Similarly, carvacrol and chlorothymol have been reported to influence radioligand binding to GABA A Rs in a manner that is consistent with them acting as positive allosteric modulators (Reiner et al, 2013). Carvacrol has also been reported to inhibit the binding of nicotine to nAChRs via a site that is distinct from the orthosteric binding site (Tong et al, 2013).…”

“…In addition, both carvacrol and thymol are used as acaricides to control mite (Varroa destructor) infestation of honeybee hives (Damiani et al, 2009). There is evidence that carvacrol and thymol are positive allosteric modulators of both invertebrate and mammalian GABA A Rs (Priestley et al, 2003;García et al, 2006;Reiner et al, 2013). In addition, carvacrol has also been reported to inhibit the binding of nicotine to nAChRs via a site that is distinct from the conventional orthosteric binding site (Tong et al, 2013).…”

Effects of Gabaergic Phenols on Phospholipid Bilayers as Evaluated by <sup>1</sup>H-NMR

“…In addition, by using Langmuir films and epifluorescence images, we described that all the compounds were able to diffuse into the membrane, placing themselves between phospholipid molecules probably at the head-group region [14]. Finally, by means of fluorescence anisotropy studies we have recently found that all five compounds were able to decrease the microviscosity of artificial membranes [8].…”

“…These compounds are GABA-Rs allosteric modulators as they bind to distinct sites to potentiate GABA-evoked currents [1][2][3][4][5]. The phenols propofol and thymol, and lately carvacrol, eugenol and chlorothymol, have been shown to act as positive allosteric modulators on this receptor [6][7][8].…”