Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.
"In 2004, Wan and collaborators synthesized the first selective nonpeptide AT 2 receptor agonist, called compound 21 (C21) , now renamed M024 . Since then, an increasing number of studies have used C21/M024 for both in vitro and in vivo studies (see further below) to better investigate the selective role of the AT 2 receptor (for review, see  ). "
[Show abstract][Hide abstract] ABSTRACT: Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT(1)) receptor and the type 2 (AT(2)) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT(2) receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT(2) receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT(2) receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT(2) receptor in the brain must also consider the Ang IV/AT(4) receptor.
International Journal of Hypertension 12/2012; 2012:351758. DOI:10.1155/2012/351758
"In this regard, we have characterized the properties of several non-peptide compounds. One of these ligands, C21 (compound 21) (Wan et al., 2004) renamed M024 (Georgsson et al., 2007), acts as an angiotensin AT 2 receptor agonist. Using the neuronal/glioma NG108-15 hybrid cell line, we found that C21/M024 stimulates neurite outgrowth through sustained activation of p42/p44 mapk , similarly to Ang II or CGP42112A (Wan et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that angiotensin II (Ang II), through binding to the type 2 (AT(2)) receptor may have beneficial effects in various physiological and pathological situations. However, specific action presumably mediated by the angiotensin AT(2) receptor has been hampered by the absence of appropriate selective ligands. The aim of this study was to compare the biological properties of two related and selective drug-like nonpeptide AT(2) ligands, namely an agonist called M024 (also known as Compound 21) and a new ligand, presumably an antagonist, C38/M132, (originally called C38). Properties of the compounds were investigated in NG108-15 cells expressing angiotensin AT(2) receptor and known to develop neurite outgrowth upon Ang II stimulation. NG108-15 cells stimulated for three days with C21/M024 (0.1 or 100nM) exhibited the same neurite outgrowth as cells stimulated with Ang II (100nM) while co-incubation of Ang II or C21/M024 with C38/M132 (10 or 100nM) inhibited their effects, similarly to the angiotensin AT(2) receptor antagonist, PD123,319 (10µM). As Ang II, C21/M024 induced a Rap1-dependent activation of p42/p44(mapk) whereas preincubation of cells with C38/M132 inhibited p42/p44(mapk) and Rap1 activation induced by Ang II. Three-day treatment with C21/M024 or Ang II decreased cell number in culture, an effect that was rescued by preincubation with C38/M132. Taken together, these results indicate that the nonpeptide ligand C21/M024 is a potent angiotensin AT(2) receptor agonist while C38/M132 acts as an antagonist. These selective nonpeptide angiotensin AT(2) ligands may represent unique and long-awaited tools for the pursuit of in vivo studies.
European journal of pharmacology 12/2012; 699(1-3). DOI:10.1016/j.ejphar.2012.11.032 · 2.53 Impact Factor
"Anders Hallberg and colleagues, as recently summarized by Steckelings et al. (2010a,b) and Unger and Dahlof (2010), have characterized the properties of several non-peptidic compounds derived from the prototype non-selective AT1/AT2 receptor agonist L-162,313 (Wan et al., 2004; Georgsson et al., 2005, 2006; Rosenstrom et al., 2005; Wu et al., 2006; Murugaiah et al., 2007). One of these ligands, the M24 compound (originally called C21; Wan et al., 2004; Georgsson et al., 2007), exhibits high affinity for the AT2R (0.4 nM), but very low affinity for the AT1R (>10,000 nM) and acts as an AT2R agonist (Wan et al., 2004). Using a neuronal/glioma cell line (a variant of NG108-15 cells expressing only the AT2R), we found that C21/M24 stimulates neurite outgrowth through sustained activation of p42/p44mapk, as observed with Ang II or CGP42112A (Wan et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer's disease (AD). Angiotensin II (Ang II) is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type 1 receptor (AT1R) and the type 2 receptor (AT2R). Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs) attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by non-peptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in AD and other neurological cognitive disorders.
Frontiers in Endocrinology 08/2011; 2:17. DOI:10.3389/fendo.2011.00017
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