Therapeutic targeting of TRP channels--the TR(i)P to pain relief

Following the cloning and characterization of the transient receptor potential vanilloid 1 (TRPV1), a growing body of research has identified the important role of TRPV1 and related channels in diverse physiological functions including temperature transduction and pain signalling. As a result, there has been a great deal of interest by the pharmaceutical industry to develop small molecule modulators of the activity of these channels for potential therapeutic use. While most of the efforts have focused on examining the role of TRPV1 in nociception, more recent work has begun to assess the therapeutic utility of targeting other TRP channels. This manuscript is aimed at introducing the reader of this special issue to the promising new developments and findings as well as emerging challenges in the targeting of the thermoTRP family of receptors for clinical therapeutic use. This chapter will focus on current efforts from the pharmaceutical industry to develop highly potent and efficacious compounds that modulate TRP channel function. In particular, this chapter will highlight recent drug discovery activities around the transient receptor potential vanilloid family members TRPV1, TRPV3, and TRPV4, the transient receptor potential ankyrin family member TRPA1, and the transient receptor potential melastatin family member TRPM8. The majority of the work included in this chapter will focus on recent findings in the development of TRP modulators for pain indications; however, for certain targets where data exist, other indications will be discussed. The increasing number of small biotech and pharmaceutical companies pursuing targets in these families of ion channels highlights the perceived importance of these targets in the treatment of a variety of disease states including inflammatory and neuropathic pain, urinary incontinence, painful bladder syndrome, and even types of prostate cancer.