AT2R (antagonist) + neprilysin/enkephalinase (dual)

Class

Dual AT2R antagonist / enkephalinase inhibitor

The renin-angiotensin system, best known for regulating blood pressure through the receptor AT1R, also includes a second receptor, AT2R, whose actions are more nuanced. AT2R is expressed on peripheral sensory neurons and certain immune cells, where its activation can sensitize pain pathways and promote inflammatory signaling, in contrast to AT1R's cardiovascular effects. Neprilysin, also called enkephalinase, is an enzyme that breaks down several signaling peptides, including natriuretic peptides and enkephalins, the body's endogenous opioid-like pain-modulating peptides. Blocking neprilysin extends the activity of enkephalins at their receptors, enhancing natural analgesic signaling. A molecule combining AT2R antagonism with neprilysin inhibition is designed to act on pain from two complementary directions: removing a receptor that promotes nociceptive sensitization while simultaneously preserving more of the body's own opioid-like peptides at the site of injury or inflammation. This dual approach is of interest for neuropathic and inflammatory pain, conditions where single-mechanism therapies, including exogenous opioids, often provide incomplete relief or carry substantial risk of tolerance, dependence, or central side effects. By pairing a peripherally-acting antagonist with an enzyme inhibitor that boosts local peptide signaling, this mechanism class aims to achieve meaningful analgesia while limiting the systemic and central nervous system exposure associated with conventional opioid therapy.