Update on Angiotensin II Subtype 2 Receptor: Focus on Peptide and Nonpeptide Agonists.

Angiotensin II (Ang II) is the most dominant effector component of the renin-angiotensin system (RAS) that generally acts through binding to two main classes of G protein-coupled receptors, namely Ang II subtype 1 receptor (AT1R) and angiotensin II subtype 2 receptor (AT2R). Despite some controversial reports, the activation of AT2R generally antagonizes the effects of Ang II binding on AT1R. Studying AT2R signaling, function, and its specific ligands in cell culture or animal studies has confirmed its beneficial effects throughout the body. These characteristics classify AT2R as part of the protective arm of the RAS that, along with functions of Ang (1-7) through Mas receptor signaling, modulates the harmful effects of Ang II on AT1R in the activated classic arm of the RAS. Although Ang II is the primary ligand for AT2R, we have summarized other natural or synthetic peptide and nonpeptide agonists with critical evaluation of their structure, mechanism of action, and biologic activity. SIGNIFICANCE STATEMENT: AT2R is one of the main components of the RAS and has a significant prospective for mediating the beneficial action of the RAS through its protective arm on the body's homeostasis. Targeting AT2R offers substantial clinical application possibilities for modulating various pathological conditions. This review provided concise information regarding the AT2R peptide and nonpeptide agonists and their potential clinical applications for various diseases.

Improved pharmacokinetics and bone tissue accumulation of Angiotensin-(1-7) peptide through bisphosphonate conjugation.

The renin-angiotensin system (RAS) has a central role in renal and cardiovascular homeostasis. Angiotensin-(1-7) (Ang1-7), one of the RAS active peptides, exerts beneficial effects through different mechanisms. These biological actions suggest that Ang1-7 is an effective therapeutic agent for treating various diseases associated with activated RAS. However, its short half-life and poor pharmacokinetics restrict its therapeutic utility. Our laboratory has successfully synthesized and characterized an Ang1-7 conjugate (Ang Conj.) with a prolonged half-life and improved pharmacokinetics profile. The Ang Conj. has been prepared by PEGylation of Ang1-7 and conjugation with a bisphosphonate using solid-phase peptide synthesis and characterized by HPLC and mass spectrometer. The compound's stability has been tested in different storage conditions. The bone binding capacity was evaluated using a hydroxyapatite assay. Pharmacokinetic and tissue distribution studies were performed using iodinated peptides in rats. Ang Conj. was synthesized with > 90% purity. Bone mineral affinity testing showed Ang Conj. exhibited significantly higher bone mineral affinity than Ang1-7. The Ang Conj. remained stable for more than a month using all tested storage conditions. The Ang Conj. demonstrated higher affinity to bone, a longer half-life, and better bioavailability when compared with the native peptide. These results support that conjugation of Ang1-7 with bisphosphonate enables it to utilize bone as a reservoir for the sustained delivery of Ang1-7 to maintain therapeutic plasma levels. High chemical stability and about five to tenfold prolongation of Ang Conj. plasma half-life after administrations into rats proves the effectiveness of our approach.

Targeting the Protective Arm of the Renin-Angiotensin System: Focused on Angiotensin-(1-7).

The in vivo application and efficacy of many therapeutic peptides is limited because of their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classic and protective arms. The balance between these two arms is critical for the homeostasis of the body's physiologic function. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathologic conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of angiotensin-(1-7) [Ang-(1-7)], a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings. SIGNIFICANCE STATEMENT: Ang-(1-7) is a unique peptide component of the renin-angiotensin system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.

Craving and Drug Reward: A Comparison of Celecoxib and Ibuprofen in Detoxifying Opiate Addicts.

Objective: Craving for substance abuse is a usual and complicated problem in patients, with opioid addiction who are in opioid detoxifying process. Craving has been added as one of the diagnostic criteria of substance use disorders in DSM-5. The present trial aimed at comparing the effects of celecoxib versus ibuprofen in reducing pain and decreasing the desire to use opiates in patients undergoing opiate detoxification (n = 32). Method: A total of 32 patients (both inpatients and outpatients), who were undergoing opiate detoxification procedure and met the inclusion criteria entered this 4- week study. Participants who suffered from pain due to opiate withdrawal were randomized into 2 groups: Group 1 received celecoxib 200 milligrams once per day and group 2 received ibuprofen 400 milligrams 4 times per day. Self-reported Desire for Drug Questionnaire (DDQ) and 0-10 numeric pain scale were used at baseline and at the end of the study to evaluate changes in opiate craving and pain, respectively. Data analysis was done by SPSS-21 statistical software. Results: In this study, 16 patients received celecoxib 200 milligrams once daily, and 16 received ibuprofen 400 milligrams 4 times daily. After 4 weeks of treatment with both ibuprofen and celecoxib, the results revealed that celecoxib and ibuprofen equally reduced the pain symptoms. After 4 weeks of treatment, with either ibuprofen or celecoxib, significant improvement was observed in decreasing the craving in the celecoxib group, but not in the ibuprofen group. Conclusion: The study revealed a significant difference between the celecoxib and ibuprofen group in reducing craving in patients with opiate craving after 4 weeks of treatment. However there were no significant differences between these two groups in reducing pain.