Natural Compounds and Synthetic Drugs Targeting the Ionotropic Cannabinoid Members of Transient Receptor Potential (TRP) Channels

The transient receptor potential (TRP) channels are polymodal cation-permeable receptors involved in the transduction of both physical (temperature, pressure, pH) and chemical stimuli. Six of these membrane proteins, i.e. TRPV1-4, TRPA1 and TRPM8, are referred to as thermoTRPs due to their involvement in thermosensation and in the nociception evoked by noxious cold and heat. Such receptors are also termed "ionotropic cannabinoid receptors" (icTRPs), to highlight the role of these channels in the (endo)cannabinoid signaling. Besides their physiological role, icTRPs represent relevant therapeutic targets for a variety of diseases such as neuropathic pain, inflammation, cancer, and respiratory diseases. Bioactive molecules targeting these receptors form a variegate landscape, spanning from natural compounds to endogenous ligands up to synthetic modulators. Due to the role of these channels in the perception of smell and taste, many natural agonists have been found in spices and foods. The discovery of such "spicy" receptors prompted the search for endogenous modulators, such as endocannabinoids, and paved the way for the chemical modification of natural scaffolds, as well as the search for novel chemotypes by high-throughput screening followed by lead optimization to improve their potency/selectivity, with the aim of developing efficacious pharmacological tools or drugs.