Modulation of thermoreceptor TRPM8 by cooling compounds

Abstract

ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling. TRPM8 is activated by innocuous cooling (<30 °C) and contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia and is a receptor for menthol and icilin (mint-derived and synthetic cooling compounds, respectively). TRPA1 (Ankyrin family) is activated by noxious cold (<17 °C), icilin, and a variety of pungent compounds. Extensive amount of medicinal chemistry efforts have been published mainly in the form of patent literature on various classes of cooling compounds by various pharmaceutical companies; however, no prior comprehensive review has been published. When expressed in heterologous expression systems, such as Xenopus oocytes or mammalian cell lines, TRPM8 mediated currents are activated by a number of cooling compounds in addition to menthol and icilin. These include synthetic p-menthane carboxamides along with other class of compounds such as aliphatic/alicyclic alcohols/esters/amides, sulphones/sulphoxides/sulphonamides, heterocyclics, keto-enamines/lactams, and phosphine oxides. In the present review, the medicinal chemistry of various cooling compounds as activators of thermoTRPM8 channel will be discussed according to their chemical classes. The potential of these compounds to emerge as therapeutic agents is also discussed.

Keywords: TRPA1; TRPM8; Thermoreceptors; cooling compounds; icilin; menthol.

Figure 1

(A) Temperature response profiles of heat- or cold-induced activation of TRPV1, TRPV2, TRPV4, and TRPM8 at a holding potential of 60 mV in HEK293 cells expressing these ion channels. Dotted lines indicate the threshold temperatures for activation. (B) Temperatures causing pain and activating six TRP channels. Dotted lines indicate that threshold temperatures for activation of TRPV1 and TRPM8 are not fixed but changeable in the presence of other stimuli.

Figure 2

TRPM8 receptor channel.

Figure 3

Naturally occurring monoterpenes with physiological cooling property.

Figure 4

Menthol esters.

Figure 5

Menthol ethers and other related acyclic ethers.

Figure 6

N-Substituted p-methane-3-carboxylic acid esters.

Figure 7

N-Substituted p-methane-3-carboxamides.

Figure 8

2/3-Substituted p-menthane-3-ols.

Figure 9

Acyclic/alicyclic carboxamides/ureas.

Figure 10

Sulphones, sulphoxides, and sulphonamides.

Figure 11

Alicyclic/cyclic alcohols, carboxylic acids, esters, and amides.

Figure 12

Heterocyclic cooling compounds.

Figure 13

Cyclic keto-enamines and N-aryl lactams.

Figure 14

Miscellaneous cooling compounds.

Figure 15

Trp-p8 antagonists.

Figure 16

TRPM8 antagonists.