CGP42112: the full AT2 receptor agonist and its role in the renin–angiotensin–aldosterone system: no longer misunderstood

Abstract

For years, the AT2R-selective ligand CGP42112 has been erroneously characterized as a partial agonist, partly due to its ability to also interact with the AT1R at high concentrations. As late as 2009, it was still being characterized as an antagonist as well. In this perspective/opinion piece, we try to resolve the ambiguity that surrounds the efficacy of this compound by extensively reviewing the literature, tracing its beginnings to 1989, showing that CGP42112 has never been convincingly shown to be a partial agonist or an antagonist at the AT2R. While CGP42112 is now routinely characterized as an AT2R agonist, regrettably, there is a paucity of studies that can validate its efficacy as a full agonist at the AT2R, leaving the door open for continuing speculation regarding the extent of its efficacy. Hopefully, the information presented in this perspective/opinion piece will firmly establish CGP42112 as a full agonist at the AT2R such that it can once again be used as a tool to study the AT2R.

Angiotensin-Related Peptides and Their Role in Pain Regulation

“…Since the analgesic effects of Ang II and III are suppressed by AT1 receptor and AT2 receptor antagonist losartan and CGP42,112A, respectively, it could be concluded that both receptors are involved. However, it has been suggested that CGP42,112A may be a full agonist of the AT2 receptor [18], indicating the need for further studies on the specific role of AT2. Since losartan exacerbated incision-induced allodynia even when administered alone [16], it could be concluded that endogenous local Ang-producing system works in the analgesic direction in PAG via AT1 receptors (Figure 2).…”

The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

“…In vascular smooth muscle cells (VSMCs), Ang II binds to AT1R, activating phospholipase C and raising intracellular [Ca +2 ], leading to vasoconstriction [3,4]. Activating AT2R, Ang II lowers blood pressure by vasodilatation and nitric oxide (NO) release [11]. Also, AT2R is involved in wound healing and tissue remodeling [12].…”