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Special issue: Allosterism and Collateral Efficacy
Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

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Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy – instead of partial antagonism – and they can affect – and often improve – the potency of the endogenous agonist. Surprisingly, the apparent binding sites of several ordinary allosteric enhancers and ago-allosteric modulators seem to overlap with those of the endogenous agonists. Different molecular scenarios are proposed to explain this discrepancy from classical allosteric models. In one scenario, the ago-allosteric modulator can interchange between different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, ‘allosteric’ protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery process because a compound that acts with – rather than against – the endogenous agonist could be an optimal agonist drug.

Section snippets

Ago-allosteric modulator versus ‘ordinary’ allosteric modulator or enhancer

According to the International Union of Pharmacology (IUPHAR: http://www.iuphar.org/) committee on quantitative pharmacology, allosteric enhancers (see Glossary) are defined as ‘modulators that enhance the affinity and/or efficacy of the orthosteric ligand while having no effect on their own’ [1]. Although there have been sporadic reports of allosteric enhancers having agonistic properties on their own 2, 3, this phenomenon had not attracted a great deal of attention and was, for example,

Ago-allosteric modulator versus allosteric agonist

The IUPHAR committee clearly differentiates between allosteric enhancers, which have no effect on their own, and ‘allosteric agonists’, which are defined as ‘ligands that are able to mediate receptor activation in their own right by binding to a recognition domain on the receptor macromolecule that is distinct from the primary (orthosteric) site’ [1]. This definition – and the differentiation of allosteric agonists from allosteric enhancers – has been generally accepted in the field [4].

Where do classical allosteric modulators bind to the receptor?

7TM receptors are subject to allosteric modulation by, for example, G proteins and Na+. Such modulation occurs through classical allosteric mechanisms because the binding sites for these agents are separate from the orthosteric binding site for the endogenous agonist (Figure 1). Thus, whereas agonists bind to the main ligand-binding crevice or even more extracellularly [20], the G protein – which allosterically influences agonist binding and is, itself, also allosterically influenced by agonist

Where do ago-allosteric modulators bind at the receptor?

Only a few ago-allosteric modulators have been characterized with regard to binding site but, in all cases, a considerable overlap was found with the orthosteric binding site for the endogenous agonist 8, 9, 34, 35, 36. For example, the highly selective M1 agonist AC-42, which was recently found to act as an allosteric ligand 7, 34, shares several presumed interaction points with the agonist carbachol on the inner face of transmembrane domain (TM)-III. Mutations at some of these positions

Ago-allosteric modulators: the optimal agonist drug for patients?

In the agonist drug discovery process, attention with regard to optimizing effects on the target receptor is normally directed towards obtaining sufficiently high potency and efficacy. It is, for example, generally appreciated that agonists showing only partial efficacy compared with the endogenous agonist should be avoided – unless there are special reasons to aim for such compounds. This is because, according to classical receptor theory, partial agonists are expected to act as partial

Acknowledgements

The research projects in the laboratories of T.W.S. and B.H. on which this article is based are supported by grants from the Danish Medical Research Council, The Novo Nordisk Foundation and the Lundbeck Foundation.

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