Stereo‐selective activity of menthol on GABA_A receptor

Abstract

Menthol is a naturally occurring compound, which has three chiral centers that define eight possible optically actives stereoisomers. Neuroactivity of menthol and related agents by affecting neuronal intracellular signaling or by modulation of neurotransmitter-gated currents has been reported. Furthermore, stereo-selectivity of menthol in its analgesic activity as well as in its sensory properties and other biological activities was also described. The present study is the first contribution to the description of stereo-selectivity of GABA(A) receptor against the most possible isomers of menthol, discussed in terms of their chirality. The results showed that only (+)-menthol, among the five stereoisomers analyzed, was active, stimulating in a dose-response manner the binding of an allosteric GABA(A) receptor ligand. Taking into account these results, and comparing them with those of some active phenolic compounds, it is strongly suggested that the existence of a relative spatial location of its substituents with respect to the ring (equatorial position of all substituents and (1S,2R,5S)-configuration) as well as the presence in the cyclic molecule of an aliphatic non polar group (isopropyl) with free rotation near to a polar group (hydroxyl) are crucial points to demonstrate activity on the receptor.

TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain

“…In addition to activating TRPM8 channels, these concentrations are sufficient or by far exceed the concentrations needed to exert pharmacological effects on other targets implicated as mediators of menthol-induced analgesia, including voltage-dependent Ca 2+ channels, GABA A -receptors, sodium channels, peripheral nicotinic acetyl choline receptors or serotonin-gated ion channels [11; 19; 22; 24; 49; 52; 63; 67]. The role of these alternative targets in L-menthol-induced analgesia should have been unmasked in Trpm8−/− mice.…”

“…Menthol was found to inhibit neuronal voltage-dependent Ca 2+ channels [49; 52]. Menthol was shown to activate GABA A -receptors, which may induce central inhibition of nociception [11; 63; 67]. Menthol may also elicit analgesia by inactivating voltage-gated sodium channels mediating action potentials in sensory neurons [19].…”

Cellular and Molecular Targets of Menthol Actions

“…In another investigation, it was reported that only (+)-menthol, among the five menthol stereoisomers studied, was found to be active in potentiating the binding of [ 3 H]-flunitrazepam, an allosteric ligand for GABA A receptor (Corvalán et al, 2009) while (+) and (−)-neomenthol were found to be inactive. In another radioligand binding study, monoterpenes such as carvacrol, citronellic acid, 1,8-Cineole, thymol, and pulegone significantly increased the specific binding of [ 3 H]-tbutylbicycloorthobenzoate (TBOB), a non-competitive inhibitor of picrotoxin.…”

“…For instance, a recent investigation has identified transmembrane residues that eliminate the agonist action of thymol and carvacrol on human 5-HT 3 receptors, or confer this property on mouse 5-HT 3 receptors that are previously insensitive to these compounds (Lansdell et al, 2015). Moreover, at least in some investigations, stereoselectivity for the effects of monoterpenes was demonstrated (Hall et al, 2004; Watt et al, 2008; Corvalán et al, 2009; Gonçalves et al, 2010; Heimes et al, 2011; Kawasaki et al, 2013; Walstab et al, 2014). Furthermore, specific amino acid residues mediating the actions of monoterpenes were identified on 5-HT 3 (Lansdell et al, 2015) and GABA A receptors (Watt et al, 2008).…”

Effects of menthol stereoisomers on the growth, sporulation and fumonisin B1 production of Fusarium verticillioides

“…The chirality of the odorants, in addition, exerts an influence on their mode of action, indicating that the antipodes may behave differently (Lahlou, 2004). Moreover, differences in the sensory properties and biological activities between pairs of menthol enantiomers have also been previously reported (Corvalán, Zygadlo, & García, 2009;Perillo & Zygadlo, 2005;Turina, Nolan, Zygadlo, & Perillo, 2006). However, the stereoselective activities of the menthol stereoisomers on the fungal growth and secondary metabolite biosynthesis have not been extensively explored.…”