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  • br Allosteric inhibitors In general


    Allosteric inhibitors In general, candidate drugs that bind to a GPCR at a site that is distinct (allosteric site) from the binding site of the endogenous agonist (orthosteric site) are attracting increasing attention 39, 42, 58. Allosteric modulators display saturability of their effect, probe dependence, differential effects on the affinity and efficacy of orthosteric ligands, and system dependence 39, 42, 58. In 2000, it was reported that the effects of salicylates on ETA meet some of these criteria 45, 46. In addition, they promoted the dissociation of ET1–ETA, and thus accelerated the fading of vasoconstrictor responses initiated by ET1 and enhanced the inhibitory effects of the prototype ERA BQ123 45, 46. Important criteria of allosteric modulation such as probe (or agonist) dependence and the saturability of effects were not addressed. The structure–activity relationship for salicylates differs from that of their best-known target (cyclo-oxygensases) and millimolar rather than micromolar concentrations of the compounds are required for their proposed allosteric effect on ETA. It is therefore not likely that allosteric modulation of ETA function contributes to therapeutic effects of these aspirin-like compounds in patients. These observations suggest the existence of an allosteric modifier site on ETA that recognizes salicylate-like molecules.
    Physiological antagonism Tight receptor binding and long-lasting agonism by an endogenous signaling molecule such as ET1 are not compatible with homeostatic control of cardiovascular function in vivo. We therefore evaluated candidate endogenous counterbalancing mechanisms for specific inhibition of ET1 receptor function [16]. We tested whether one or more vasodilator compounds that can be produced in blood vessels could terminate arterial contractile responses initiated by ET1. Agents were either exogenously administered to isolated arteries or were endogenously released using accepted stimuli that act indirectly, such as a83 01 and capsaicin 16, 59, 60, 61. Both endothelium-derived relaxing factors and vasodilator neuropeptides were considered. In the endothelium, nitric oxide (NO) (i) inhibits the synthesis and release of ET1 and (ii) is produced in response to ET1 acting on endothelial ETB11, 62. Endothelium-derived NO and hyperpolarizing factor relax the contractile responses of arterial smooth muscle to ETA stimulation 16, 61, 63. Endothelium-derived relaxing factors can thus be important functional antagonists of ET1 responses. It has been reported that this is also the case in human conductance and resistance coronary arteries [64]. However, in contrast to consequences of ET1-induced signaling, ET1–ETA interaction does not seem to be modified by endothelium-derived relaxing factors. The endothelium-dependent vasodilator acetylcholine did not promote dissociation of ET1–ETA complexes (Figure 3) [16], and NOS and COX inhibition did not modify the potency of contractile responses to ET1 and their irreversibility 16, 61. In the kidneys, sensorimotor nerves counterbalance effects of ET1 through release of one of their neurotransmitters, calcitonin-gene-related peptide (CGRP) [65]. In rat mesenteric arteries, stimuli of peri-arterial sensorimotor nerves and exogenous CGRP relax contractile responses to ET1 more potently than responses to other vasoconstrictors [61]. CGRP receptor stimulation by both exogenous and endogenously released neuropeptide promotes dissociation of arterial smooth muscle ET1–ETA complexes [16]. Because CGRP acts on its own heterotrimeric GPCR [38] and not directly on ETA, these observations illustrate cross-talk between peptidergic GPCRs that results in reduced affinity (increased rate of dissociation) of one of them (ETA) for its endogenous agonist (ET1), which represents indirect allosteric modulation (Figure 3, Figure 4). The signal transduction involved in this CGRP–ETA crosstalk differs from the mechanisms underlying the general vasodilator effects of CGRP [66]. It does not involve adenylyl cyclase, cAMP, NO or activation of ATP-sensitive K+ channels [16]. Whether it is due to (i) direct interaction between the two types of receptors, (ii) a receptor-activity-modifying protein or (iii) an as yet unknown second messenger could be addressed in cells that express both types of receptors and in membrane preparations of these cells. It remains to be established whether CGRP–ETA crosstalk is an incidental oddity of the rat mesenteric artery or if it also applies to other vascular beds and other species and if it is sufficiently widespread and powerful to result in systemic cardiovascular effects. Nevertheless, it illustrates the potential for allosteric mechanisms triggered not only by exogenous compounds (e.g. salicylates), but also by endogenous systems (e.g. CGRP) (Figure 4). It is noteworthy in this respect that peri-arterial sensorimotor nerves are acted on by active ingredients of chili peppers, mustard, wasabi and garlic 67, 68. These stimulate TRP channels on the nerves, which leads to release of neuropeptides (including CGRP). Some of the health benefits associated with consumption of these foods might involve an indirect (through CGRP) but selective anti-endothelinergic component.