Small Molecule Angiotensin II Type 2 Receptor (AT<sub>2</sub>R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats

Smith, Maree T.; Wyse, Bruce D.; Edwards, Stephen R.

doi:10.1111/pme.12063

Cited by 84 publications

(126 citation statements)

References 20 publications

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“…bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent mechanical hypersensitivity in the ipsilateral (injured side) hindpaws. 41 The ED 50 s for EMA200, EMA300, and EMA400 for evoking pain relief were 3.2, 0.78, and 0.01 mg/kg, respectively, showing that EMA400 is ;250-fold more potent than EMA200 and ;60-fold more potent than EMA300 in this model. 41 …”

Section: Chronic Constriction Injury Of the Sciatic Nerve In The Ratmentioning

confidence: 96%

“…41 The 10,000-fold specificity of EMA401 at the AT 2 over the AT 1 receptor is due to its very low binding affinity at rat and human AT 1 receptors (IC 50 values .50 mM) ( Table 1). 41 5. Analgesic efficacy in rodent models of peripheral neuropathic pain…”

Section: Radioligand Bindingmentioning

confidence: 97%

“…4) at the cloned rat AT 2 receptor are 3 to 4 orders of magnitude higher than at the cloned rat AT 1 receptor ( Table 1). 41 Importantly, the drug candidate, EMA401, has the same binding affinity (39 nM) at both rat and human AT 2 receptors ( Table 1). 41 The 10,000-fold specificity of EMA401 at the AT 2 over the AT 1 receptor is due to its very low binding affinity at rat and human AT 1 receptors (IC 50 values .50 mM) ( Table 1).…”

Section: Radioligand Bindingmentioning

confidence: 98%

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Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Smith

Anand

Rice

2016

Pain

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Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain. One notable exception is the angiotensin II type 2 (AT2) receptor that has clinical validity on the basis of a successful double-blind, randomized, placebo-controlled, clinical trial of EMA401, a highly selective, orally active, peripherally restricted AT2 receptor antagonist in patients with postherpetic neuralgia. In this study, we review research to date on target validation, efficacy, and mode of action of small molecule AT2 receptor antagonists in rodent models of peripheral neuropathic pain and in cultured human sensory neurons, the preclinical pharmacokinetics of these compounds, and the outcome of the above clinical trial.

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Section: Chronic Constriction Injury Of the Sciatic Nerve In The Ratmentioning

confidence: 96%

Section: Radioligand Bindingmentioning

confidence: 97%

Section: Radioligand Bindingmentioning

confidence: 98%

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Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Smith

Anand

Rice

2016

Pain

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“…AT2 receptor became new therapeutic target for the treatment of neuropathic pain. A few molecules like PD123319 [16,17] and EMA401 [18] are in clinical trials but treatment is limited due to poor efficacy and unfavourable side effects.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

Singh

Karnik

2017

J Cell Signal

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Angiotensinogen -a serpin family protein predominantly produced by the liver is systematically processed by proteases of the Renin Angiotensin system (RAS) generating hormone peptides. Specific cell surface receptors for at least three distinct angiotensin peptides produce distinct cellular signals that regulate system-wide physiological response to RAS. Two well characterized receptors are angiotensin type 1 receptor (AT1 receptor) and type 2 receptor (AT2 receptor).They respond to the octapeptide hormone angiotensin II. The oncogene product MAS is a putative receptor for Ang (1-7). While these are G-protein coupled receptors (GPCRs), the in vivo angiotensin IV binding sites may be type 2 trans-membrane proteins. These four receptors together regulate cardiovascular, hemodynamic, neurological, renal, and endothelial functions; as well as cell proliferation, survival, matrix-cell interactions and inflammation. Angiotensin receptors are important therapeutic targets for several diseases. Thus, researchers and pharmaceutical companies are focusing on drugs targeting AT1 receptor than AT2 receptor, MAS and AngIV binding sites. AT1 receptor blockers are the cornerstone of current treatment for hypertension, heart failure, renal failure and many types of vascular diseases including atherosclerosis, aortic aneurism and Marfan syndrome.

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“…Small molecule angiotensin II type 2 receptor (AT 2 R) antagonists have also been proposed as analgesics for neuropathic pain [Smith et al 2013]. Most recently, a high-profile double-blind placebo-controlled trial demonstrated the efficacy of EMA401, a novel AT 2 R antagonist, in the treatment of PHN and this drug remains in development as a therapeutic agent for neuropathic pain [Rice et al 2014].…”

Section: Future Directionsmentioning

confidence: 99%

Treatment of painful diabetic neuropathy

Javed

Petropoulos²,

Alam

et al. 2014

Therapeutic Advances in Chronic Disease

183

129

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Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldosereductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists.

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Small Molecule Angiotensin II Type 2 Receptor (AT₂R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats

Abstract: The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

Cited by 84 publications

References 20 publications

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

Treatment of painful diabetic neuropathy

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Small Molecule Angiotensin II Type 2 Receptor (AT2R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats

Abstract: The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

Cited by 84 publications

References 20 publications

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain

Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

Treatment of painful diabetic neuropathy

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Product

Resources

About

Small Molecule Angiotensin II Type 2 Receptor (AT₂R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats