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  • Soon after the discovery of


    Soon after the discovery of ET1 and the cloning of its ETA and ETB receptors, low-molecular-weight compounds were identified that can prevent the binding and effects of radioactively labeled ET1 3, 5, 6, 8. Initially, these ERAs resulted from screening efforts (e.g. BQ123 39, 49 and bosentan [50]). Subsequently, rational drug design focused on the C-terminal hexapeptide that is common to all endogenous ET isopeptides was applied [51]. Today, several classes of peptidergic, nonpeptidergic, hydrophilic, lipophilic and orally active ERAs are available [52]. Some of these do not discriminate between ET receptor subtypes, whereas others display selectivity for either ETA or ETB. One ERA, bosentan (Tracleer®), is registered worldwide for application in pulmonary hypertension. Several others are in advanced clinical development 6, 8, 52. The literature on these agents tends to suggest that all ERAs act as neutral competitive antagonists. However, ERAs can prevent agonist binding, but do not reverse established agonist–receptor complexes in membrane preparations 31, 45 or in tissue [16]. This adds evidence of the tight nature of the agonist–receptor complexes. As a result, certain ERAs prevent responses to ET1 but do not influence responses that were initiated by the peptide [53]. Surprisingly, in most cases ERAs not only prevent but also reduce (albeit to a smaller extent) ET1-induced effects in vitro and in vivo48, 54. We recently reported such a situation in isolated resistance BS-181 mg using a non-selective ERA, the pyrimidine sulfonamide bosentan, and three ETA-selective ERAs, the cyclic pentapeptide BQ123, BS-181 mg the pyrazole SB234551 and the butenolide PD156707 [16]. For all four compounds, we observed partial and reversible relaxation of the contractions during and after exposure to ET1 (Figure 3). This was not accompanied by reversal of the binding of fluorescently labeled ET1 [16]. Effects of different ERAs differ in the same test system (e.g. FR139317 vs BQ123, bosentan, PD156707 and SB234551 in rat mesenteric arteries 16, 53) and different effects were obtained with the same ERA in different preparations (e.g. PD156707 in rat mesenteric arteries and human mammary arteries 16, 55). Interpretation of the effects of ERAs will thus have to include their system dependence, which ranks among the criteria for allosteric modulation. Two mechanisms can explain the actions of ERAs on ETA. The low-molecular-weight compounds either (i) compete at only one of the orthosteric binding domains of ETA or (ii) bind at a distinct allosteric site that modulates the affinity and efficacy of the orthosteric domains (Figures 1c,d and 2). In the first model [16], ERAs and ET1 compete at a domain on ETA that would correspond to R-et in Figure 1, which is a prerequisite for irreversible binding of ET1 at another domain (represented by R-ET in Figure 1). Binding at this domain can modulate the activation triggered by the occupied second domain. In this view, ERAs can act as either neutral competitive antagonists or inverse agonists on the orthosteric domain, depending on whether the orthosteric domains display cooperativity for receptor activation. The notion that low-molecular-weight ERAs bind to an orthosteric domain is suggested by observations that at least some of them (e.g. BQ123 and ABT-627) promote internalization of ETA56, 57. In the second model, ERAs act as allosteric inhibitors, reducing the affinity and/or efficacy of the orthosteric binding domains within the orthosteric binding site (Figure 1d). Molecular modeling studies indicate that the binding site of some ERAs does not fully coincide with the ET1 binding domains 27, 30. It has been proposed that the binding site of some ERAs is located somewhat deeper in the cleft between TMs 1, 2, 3 and 7 of the ETA. If the ERA and ET1 binding sites partly overlap, then the two models are not mutually exclusive. Furthermore, both models might not equally apply to distinct classes of ERAs. This remains to be established. There is currently no nomenclature in pharmacology that discriminates between antagonists that bind to either (i) one of two orthosteric binding domains or (ii) an allosteric binding site that is topographically distinct from both of the two orthosteric binding domains.