The vanilloid receptor VR1 is a polymodal nociceptor sensitive to capsaicin, protons, and heat. Because VR1 represents an attractive therapeutic target for conditions ranging from long-term pain to bladder hyperreflexia, we and other groups have sought to develop novel ligands with enhanced potencies and novel pharmacological properties. Here, we characterize two compounds, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)
Ca2ϩ uptake in response to capsaicin were 67.3 Ϯ 24.9 nM and 3.4 Ϯ 0.5 nM, respectively. Protons, temperature, and protein kinase C all function as coactivators/modulators of rVR1. All enhanced the extent of partial agonism of JYL827 and JYL1511. Thus, at pH 5.5, for example, the extents of partial agonism increased to 54.9 Ϯ 2.5% and to 90.7 Ϯ 1.7%, respectively, relative to the response elicited by 300 nM capsaicin. The extents of partial antagonism decreased correspondingly. Compounds such as JYL827 and JYL1511 now permit exploration of the potential utility of partial agonists of rVR1 in animal models. Our results emphasize, moreover, the strong dependence of such partial agonists on other modulators of rVR1 and predict that their biological behavior will depend strongly on biological context.The vanilloid receptor VR1 has attracted great attention, because of both its biological function and its therapeutic potential. VR1, also called vanilloid receptor type 1, a member of the transient receptor potential family of ion channels, is a modestly calcium-selective ion channel located in C-fiber and A␦ sensory neurons as well as in a growing number of other sites such as the central nervous system or the bladder (Szallasi, 2001). VR1 functions as an integrative transducer for a range of nociceptive signals, including heat, protons, endogenous ligands, such as lipoxygenase products or anandamide, and exogenous compounds such as capsaicin or resiniferatoxin (Julius and Basbaum, 2001). Activation of VR1 by capsaicin may be followed by subsequent loss of responsiveness, depending on dose, duration of application, and other conditions, and reflects a combination of overlapping mechanisms, such as dephosphorylation or calcium toxicity to the neurons (Szallasi and Blumberg, 1999). This desensitization/defunctionalization by capsaicin has been exploited to treat a variety of conditions in which C-fiber sensory neurons are involved, such as pain associated with arthritis, cystitis, human immunodeficiency virus, and diabetic neuropathy (Robbins, 2000). Although capsaicin has made it possible to identify an exciting series of potential therapeutic applications, its utility has been limited by its somewhat modest potency, by the initial pain occasioned upon initial application, and by its metabolic lability (Szallasi, 2001). Attention has therefore been directed at the development and characterization of novel analogs of capsaicin. Although still in the early stages, much progress has been made.Ligands have been identified with much greater potency for VR1 than that displayed by capsaicin. Resiniferatoxi...