Advantages of Allosteric Ligands

To date, GPCR pharmacology has primarily been focused on the discovery and characterization of ligands that target the endogenous agonist binding site. This approach to drug discovery has yielded many highly efficacious and therapeutically useful compounds. However, for some GPCRs, the identification of compounds with the desired pharmacological properties remains elusive. A common obstacle is the development of a ligand with sufficient selectivity between subtypes of the same receptor family. The evolutionary pressure to accommodate a common endogenous ligand has meant that the orthosteric binding site is often highly conserved between receptor subtypes. In contrast, allosteric binding sites do not accommodate a common endogenous ligand and as a consequence, generally display much greater sequence divergence between receptor subtypes [77]. Therefore, targeting the allosteric binding site may represent a more successful strategy to obtain highly subtype selective ligands. The family of mAChRs (M1-M5) has high sequence homology within the orthosteric binding site [78] . However, mAChRs can also be allosterically regulated by a wide range of structurally diverse ligands through multiple allosteric binding sites [79-82]. A number of muscarinic ligands that demonstrate subtype selectivity either at the level of function or binding have been shown to have an allosteric mode of action. Allosteric modulators such as gallamine, alcuronium, and C7/3-phth have considerably higher affinity for the M2 mAChR as compared with the M5 mAChR. This binding selectivity is driven by residues that are not conserved between the receptor subtypes such as the acidic 172EDGE175, which is specific to the second ECL of the M2 mAChR [83-85]. An alternative approach for obtaining subtype selectivity is to use a bivalent ligand, the allosteric portion of which confers selectivity, whereas the orthosteric portion mediates the desired pharmacology. At the M2 mAChR, bivalent ligands have been developed using a hybrid of the potent nonselective orthosteric agonist, iperoxo, and fragments of bis(ammonio) alkane-type allosteric modulators. These compounds were full agonists at the M2 mAChR and displayed a higher affinity for the M. mAChR when compared against the M1 and M3 mAChR [86] .

Another advantage of allosteric modulators is that they have the potential to conserve the spatial and temporal signaling profile of the endogenous agonist [87]. Under normal physiological conditions, the action of an endogenous agonist is generally intermittent and is highly regulated. In contrast, exogenous agonists mediate continual receptor activation where and when they are present. Allosteric modulators that lack intrinsic efficacy have no effect on receptor function until the endogenous agonist is present. The magnitude and direction of the modulation imparted by the allosteric ligand will represent the combination of the cooperativity between ligand binding, efficacy, and activation. This aspect of allosteric modulators is particularly important when the therapeutic objective is a chronic enhancement of the action of an endogenous agonist.

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