A patent review of transient receptor potential vanilloid type 1 modulators (2014–present)

ABSTRACT

Introduction: Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel with high permeability to calcium, which is widely expressed in the central nervous system (CNS) and peripheral nervous system. Since the TRPV1 was molecularly cloned more than 20 years ago, a series of research activities have been carried out on the possibility of new drugs.

Areas covered: This review summarizes the patents on TRPV1 regulators (including agonists and antagonists) that were published during 2014–present and predicts the development direction in the future. The patent description is organized according to the applicant company and focuses on the representative compounds and their in vitro and in vivo data.

Expert opinion: At present, TRPV1 is considered to be a molecular integrator of a broad range of chemical and physical stimuli. The desensitization of nociceptive neurons caused by TRPV1 agonists and the pharmacological blockade of TRPV1 by powerful small molecular antagonists are different treatments, both of which have analgesic effects. Unfortunately, TRPV1 modulators have suffered from adverse effects related to the role of TRPV1 channel in body temperature regulation and noxious heat sensation. What we need to know is whether these adverse effects are on-target (unavoidable), and whether chemical modification can be used to avoid or reduce these adverse reactions in the process of designing drug molecules, so as to develop a TRPV1 regulator with potent analgesic effect and no obvious adverse effects. Despite the difficulties and roadblocks, TRPV1 modulators remain powerful tools in pain research and represent promising therapeutic agents.

KEYWORDS:

• Capsaicin
• transient receptor potential
• TRPV1
• TRPV1 agonist
• TRPV1 antagonist

Article highlights

• TRPV1 channel is a polymodal receptor, which means it can be activated by a wide range of physical (heat, >43°C), chemical stimuli (pH <5.9), endogenous agonists (e.g., anandamide), and a variety of irritant plant products (e.g., capsaicin, resiniferatoxin).

• TRPV1 is recognized a molecular integrator of a broad range of chemical and physical stimuli, and both agonists and antagonists of TRPV1 have potential analgesic activities.

• During the period from 2014 to 2020, some TRPV1 agonists and antagonists were disclosed in the patent. Some representative compounds have potent activity in vitro and efficacy in various pain models in vivo.

• In recent years, some TRPV1 antagonists have withdrawn from clinical trials due to adverse effects, and the attitude of researchers towards TRPV1 antagonists has changed from excitement to caution.

• Multi-target drugs which can not only play a synergistic analgesic effect, but also avoid single-target side effects will be the development trend of chronic pain treatment.

This box summarizes key points contained in the article.

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Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was financially supported by the National Natural Science Foundation of China [U1704185], the Key Scientific and Technological Project of Henan Province [202102310147] and open project [ZKF202004] of the Key Laboratory of Advanced Drug Preparation Technologies of Ministry of Education (Zhengzhou University).