Targeting angiotensin II type 2 receptor pathways to treat neuropathic pain and inflammatory pain

Abstract

Introduction: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT 2 R) antagonist. Areas covered: Herein, angiotensin II/AT 2 R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT 2 R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief. Expert opinion: The functional importance of angiotensin II/AT 2 R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT 2 R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, smallmolecule AT 2 R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT 2 R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

“…Two main lines of thought can then be followed to direct pain drug discovery strategies: the first (and most commonly followed) aims at producing compounds that can cross the BBB to directly interfere with central sensitization mechanisms, the second intends to hit the primary afferent neurons at periphery, in order to reduce or block central sensitization without the unwanted CNS side effects [87].…”

Recent advances in the management of chronic pain

“…3 The first drug in this class has shown some efficacy in diabetic neuro pathy and is now being investigated in a larger range of clinical conditions, notes Professor McMahon.…”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…In vivo studies have uncovered evidence that Angiotensin II, the receptors of which are known to be present in the DRG neurons of rats, is involved in neuronal hyperexcitabilty [189]. Angiotensin II receptor antagonists have shown to have significantly improved analgesia when compared to placebo in rat studies, making it an encouraging prosepct for providing neuropathic pain control in a novel way [189].…”

“…Angiotensin II receptor antagonists have shown to have significantly improved analgesia when compared to placebo in rat studies, making it an encouraging prosepct for providing neuropathic pain control in a novel way [189]. …”