The Other Angiotensin II Receptor: AT₂R as a Therapeutic Target

Abstract

The active hormone of the renin−angiotensin system (RAS), angiotensin II (Ang II), is involved in several human diseases, driving the development and clinical use of several therapeutic drugs, mostly angiotensin I converting enzyme (ACE) inhibitors and angiotensin receptor type I (AT 1 R) antagonists. However, angiotensin peptides can also bind to receptors different from AT 1 R, in particular, angiotensin receptor type II (AT 2 R), resulting in biological and physiological effects different, and sometimes antagonistic, of their binding to AT 1 R. In the present Perspective, the components of the RAS and the therapeutic tools developed to control it will be reviewed. In particular, the characteristics of AT 2 R and tools to modulate its functions will be discussed. Agonists or antagonists to AT 2 R are potential therapeutics in cardiovascular diseases, for agonists, and in the control of pain, for antagonists, respectively. However, controlling their binding properties and their targeting to the target tissues must be optimized.

COVID-19 and RAS: Unravelling an Unclear Relationship

“…In clinical studies, serum Ang II levels have been shown to be significantly elevated in patients with acute lung injury [36], and high serum Ang II levels have been associated with the severity and mortality of the infection [37]. While AT2R has the opposite effect of AT1R, AT2R agonists can reduce lung damage [6,38,39]. Ang-(1-7) and Mas receptor agonists alleviate acute lung injury in mouse models [39][40][41].…”

Discovery and Optimization of Highly Potent and Selective AT2R Antagonists to Relieve Peripheral Neuropathic Pain

“…In adults, AT 2 R is expressed at low levels in the normal cardiovascular system and kidneys. 3 It indicates that AT 2 R antagonists might show no potential on-target toxicity in the heart and kidneys. However, two phase II clinical trials of EMA401 have been terminated 30 , 31 very recently due to hepatotoxicity in monkeys after 39 weeks of chronic dosing, 32 which indicates that longer-term toxicity studies may be necessary for potential adverse effects.…”

Intrinsic drug potential of oxazolo[5,4‐d]pyrimidines and oxazolo[4,5‐d]pyrimidines

“…Lots of data point to a specific role for AT 2 R in neuronal tissues. AT 2 R antagonists display the antinociceptive pain properties (Smith et al., 2013), and inhibit p38 and p42/p44 MAPK and capsaicin‐evoked calcium influx in human sensory neurons which selectively express AT 2 R and not AT 1 R (Juillerat‐Jeanneret, 2020). In addition, in clinical conditions of chronic pain, TRPV1 expression is upregulated.…”