Clinical and Preclinical Experience with TRPV1 Antagonists as Potential Analgesic Agents

Abstract Identification of novel antagonists targeting the transient receptor potential vanilloid type 1 (TRPV1) protein has been at the forefront of pain research in the pharmaceutical industry for nearly 15 years. Activation of TRPV1 by algesic stimuli results in enhanced signaling in sensory neurons and contributes to sensitization of nociceptive pathways. First-generation TRPV1 antagonists were designed to block heat, capsaicin, lipid, and acid activation of the channel. Clinical development of first-generation TRPV1 antagonists were challenged by deficits in thermosensation and thermoregulation. Thereafter, it was realized that chemical matter could be selectively designed such that acid activation of the channel was maintained or only partially blocked. Distinguishing between modes of channel activation resulted in pharmacological separation of analgesic and thermoregulatory effects, and led to the discovery of ­modality-specific TRPV1 antagonists. Despite these advances, a novel analgesic acting exclusively through antagonism of TRPV1 still lacks clinical proof of concept.