Compound 21, the first orally active, selective agonist of the angiotensin type 2 receptor (AT2): implications for AT2 receptor research and therapeutic potential

Correspondence to: Prof Thomas Unger Centre for Cardiovascular Research, Institute of Pharmacology, Charité – University Medicine Berlin, Hessische Str. 3–4, 10115 Berlin, Germany. Tel: +49 30 450 525 001 Fax: +49 30 450 525 901 Email: thomas.unger@ charite.de ‘The AT2 receptor–A matter of love and hate’ was the title of a review article written some time ago – before Compound 21 was available. Indeed, for 15 years, ever since this angiotensin subtype receptor was described in 1989, it has fuelled scientific controversies for a number of reasons and, in the end, was termed as ‘enigmatic’ since its functions and signalling pathways notoriously escaped our attempts for better understanding. Even the development of angiotensin type 2 receptor (AT2) knockout mice did not shed enough light on the various enigmata of this receptor, since the ensuing phenotypes did not fully reveal its secrets. The major problem preventing further understanding of the AT2 receptor was the lack of an appropriate tool to interfere with its functions. The first compound, developed by Ciba-Geigy, was a peptide, CGP42112A, a partial agonist with high binding affinity but low potency. This peptidergic agent, while occupying the receptor at relatively low concentrations and thus apparently blocking its functions, stimulated it at higher concentrations acting as an agonist. Experimental results obtained with this compound were always difficult to interpret since the turning point between antagonism and agonism was not clearly defined. Thus, the definition of what was an agonistic and what was an antagonistic effect of the receptor could not be clearly derived from these results. Two AT2 receptor antagonists, PD123177 (no longer available) and PD123319 (still available), were more helpful, especially the former because of its higher selectivity, but it turned out that, in contrast to the angiotensin II type 1 (AT1) receptor, the selective blockade of AT2 receptors still produced equivocal results. A major reason for this disappointment was that, from the very beginning of AT2 receptor research, the expression pattern of the AT2 receptor was recognised to differ greatly from that of the AT1 receptor; while the latter is expressed abundantly and almost ubiquitously in the adult organism, the AT2 receptor is dominantly expressed during development, drastically downregulated in most organs after birth, and, in the adult, only re-expressed under conditions of ischaemic or traumatic injury (target organ damage) in many tissues. Thus, under normal physiological circumstances, this receptor can hardly be detected in many organs or cellular systems, including those of cardiovascular relevance, and its virtually non-apparent actions in the healthy state are difficult to antagonise. In addition, in most experimental settings, the fact that the natural ligand, angiotensin II, binds to both of its receptor subtypes, AT1 and AT2, with the same affinity, required blockade or elimination of the AT1 receptor to elicit the effects of angiotensin II on the remaining AT2 receptor. A further obstacle to obtaining clear experimental results on AT2 receptor function resided in the fact that this receptor, despite belonging to the large family of so-called seven transmembrane domain receptors usually coupled to G-proteins, associates directly but alternatively with at least three intracellular binding proteins, a phosphatase (SHP-1), ATBP/ATIP and PLZF, each initiating a distinct signalling pathway engendering different cellular and functional responses.