A Small Molecule Angiotensin II Type 2 Receptor (AT<sub>2</sub>R) Antagonist Produces Analgesia in a Rat Model of Neuropathic Pain by Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) and p44/p42 MAPK Activation in the Dorsal Root Ganglia

Smith, Maree T.; Woodruff, Trent M.; Wyse, Bruce D.; Muralidharan, Arjun; Walther, Thomas

doi:10.1111/pme.12157

Cited by 64 publications

(110 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of Ang II and the AT 2 receptor in adult rat lumbar dorsal root ganglia (DRGs) 27,29,40 is consistent with reports of AT 2 receptor mRNA in adult rat lumbar DRG neurons. 27,29 Using specific immunofluorescent antibodies, Ang II and the AT 2 receptors were colocalized with neuronal nuclei of substance P-containing small-tomedium sensory neurons in adult rat lumbar DRGs.…”

Section: Immunohistologysupporting

confidence: 84%

“…bolus doses of EMA300 in wild-type CCI mice was abolished in CCI mice null for the AT 2 receptor with intermediate effects in the hemizygotes. 40 Hence, affirming the role of the AT 2 receptor in the maintenance, but not the establishment, of mechanical hypersensitivity in this model. 40 …”

Section: Target Validation In Chronic Constriction Injury-mice Null Fmentioning

confidence: 88%

“…40 However, reversal of hypersensitivity evoked by single i.p. bolus doses of EMA300 in wild-type CCI mice was abolished in CCI mice null for the AT 2 receptor with intermediate effects in the hemizygotes.…”

Section: Target Validation In Chronic Constriction Injury-mice Null Fmentioning

confidence: 99%

“…The AT 2 receptor was also colocalized with neuronal nuclei of neurofilament 200kDa (NF200)-positive medium to large sensory DRG neurons, whereas Ang II was colocalized with a subset of these neurons. 29,40 Simplified schematic diagram of the renin-angiotensin system. ACE, angiotensin I-converting enzyme; AT 1 , angiotensin II type 1 receptor; AT 2 , angiotensin II type 2 receptor; GPCR, G protein-coupled receptor.…”

Section: Immunohistologymentioning

confidence: 99%

See 3 more Smart Citations

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

Smith

Anand

Rice

2016

Pain

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Immunohistologysupporting

confidence: 84%

Section: Target Validation In Chronic Constriction Injury-mice Null Fmentioning

confidence: 88%

Section: Target Validation In Chronic Constriction Injury-mice Null Fmentioning

confidence: 99%

Section: Immunohistologymentioning

confidence: 99%

See 2 more Smart Citations

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

Smith

Anand

Rice

2016

Pain

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Angiotensin II Type 2‐Receptor: New Clinically Validated Target in the Treatment of Neuropathic Pain

Rice

Smith

2014

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Neuropathic pain is a large unmet medical need. The angiotensin II type 2 (AT2 ) receptor is a target with promising data in rodent models of peripheral neuropathic pain. The AT2 receptor has attracted attention on the basis of human data from a proof-of-concept clinical trial showing that oral EMA401, a highly selective, peripherally restricted, small molecule AT2 receptor antagonist, at 100 mg twice-daily for 4 weeks, alleviated postherpetic neuralgia, an often intractable type of peripheral neuropathic pain.

show abstract

A Small Molecule Angiotensin II Type 2 Receptor (AT₂R) Antagonist Produces Analgesia in a Rat Model of Neuropathic Pain by Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) and p44/p42 MAPK Activation in the Dorsal Root Ganglia

Abstract: Augmented angiotensin II/AT₂R signaling in the DRGs of CCI rats is attenuated by EMA300 to block p38 MAPK and p44/p42 MAPK activation, a mechanism with clinical validity for alleviating neuropathic pain.

Cited by 64 publications

References 35 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

Angiotensin II Type 2‐Receptor: New Clinically Validated Target in the Treatment of Neuropathic Pain

Contact Info

Product

Resources

About

A Small Molecule Angiotensin II Type 2 Receptor (AT2R) Antagonist Produces Analgesia in a Rat Model of Neuropathic Pain by Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) and p44/p42 MAPK Activation in the Dorsal Root Ganglia

Abstract: Augmented angiotensin II/AT₂R signaling in the DRGs of CCI rats is attenuated by EMA300 to block p38 MAPK and p44/p42 MAPK activation, a mechanism with clinical validity for alleviating neuropathic pain.

Cited by 64 publications

References 35 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

Angiotensin II Type 2‐Receptor: New Clinically Validated Target in the Treatment of Neuropathic Pain

Contact Info

Product

Resources

About

A Small Molecule Angiotensin II Type 2 Receptor (AT₂R) Antagonist Produces Analgesia in a Rat Model of Neuropathic Pain by Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) and p44/p42 MAPK Activation in the Dorsal Root Ganglia