The Role of Natural Products in the Ligand Deorphanization of TRP Channels

Abstract

The ligand deorphanization of TRP channels has a tremendous potential for biomedical and nutritional research, and this review highlights the role that natural products have played in the identification of ligands for these targets and their establishment as viable candidates for drug discovery. Specific ligands have so far been discovered only for some thermoTRPs, like TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1, and the lack of selective pharmacology has been a major drawback for unraveling the biological role of TRPs. While genetic approaches (transgenic animal models) have partially compensate for the lack of ligands, the universal expression of TRPs in living systems and the success achieved with TRPV1 suggest that a systematic investigation of the natural products pool might alleviate this shortage, fostering adoption by small molecules within this class of still largely orphan biological targets.

Umbellulone modulates TRP channels

“…Pipette solution contained (millimolar): 100 K-Aspartate; 40 KCl; 2 MgCl 2 ; 4 Na 2 -ATP, 5 EGTA, and 1.2 CaCl 2 for buffering at 50 nM free Ca 2+ , 10 HEPES, and KOH to pH 7.2. [1]), its non-electrophilic derivates [2][3][4][5], and its naturally occurring analogs [6][7][8]. [ Statistical analyses Statistical analysis and graphical presentations were performed using the Origin ver.…”

Pharmacology of Vanilloid Transient Receptor Potential Cation Channels

“…Nevertheless, because these compound bind directly to TRPV1, they are conveniently considered as direct activators, in contrast to compounds that do not bind TRPV1 and affect its functioning indirectly, which are referred to as sensitizers. Because of the large body of literature on TRPV1 ligands, only the most important chemotypes and the most recent additions are discussed here (Appendino et al, 2008), covering in a more exhaustive way the issue of the topology of the vanilloid binding site.…”

“…Various lipids from the fatty acid pool have also been identified as TRPV1 activators. These compounds can be divided into conjugates of biogenic amines [e.g., N-arachidonylethanolamine (AEA,anandamide,2a), 3a), 2b), N-arachidonolylserine, and various N-acyltaurines and N-acylsalsolinols] (Appendino et al, 2008) and oxygenated eicosatetraenoic acids (Ahern, 2003;Wang et al, 2005) like the lipoxygenase products 5-, 12-, and 15-hydroperoxyeicosatetraenoic acids (5S-, 12S-, 15S-HPETE, 4a-6a) (Hwang et al, 2000), their reduced hydroxylic analogs (4b-6b), prostaglandins, and leukotriene B 4 (Huang et al, 2002). In addition, adenosine, ATP, and polyamines (such as spermine, spermidine, and putrescine) activate TRPV1, as well as acidic conditions, pH Ͻ5.9, like those observed during inflammation (Szallasi and Di Marzo, 2004;McNamara et al, 2005;Xu et al, 2005;Ahern et al, 2006;Alexander et al, 2006;Siemens et al, 2006).…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…TRPV1 activators are from the fatty acid pool and can be classified into conjugates of biogenic amines including Narachidonylethanolamine (AEA), N-arachidonoyldopamine (NADA) (Appendino et al, 2008) or oxygenated eicosatetraenoic acids like the lipoxygenase products 12-, and 15-hydroperoxyeicosatetraenoic acids (12S-, 15S-HPETE) (Ahern, 2003;Hwang et al, 2000) or their reduced hydroxylic analogues such as prostaglandins, and leukotrienes (Huang et al, 2002). In addition to these, adenosine, ATP, polyamines have agonistic activity at TRPV1.…”