Current Advances in Allosteric Modulation of Muscarinic Receptors

Abstract

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer's disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

Keywords: acetylcholine; allosteric modulation; muscarinic receptors.

Figure 1

An orthosteric ligand L binds to the receptor R with equilibrium dissociation constant K_D, and an allosteric modulator A binds to the receptor R with an equilibrium dissociation constant K_A. The orthosteric ligand L and the allosteric modulator A can bind concurrently to the receptor R to form a ternary complex LRA. Binding of one ligand to the receptor changes the equilibrium dissociation constant of the other ligand by a factor of cooperativity α [15].

Figure 2

Side view with TM6 front (left), and extracellular view (right) of the orthosteric (yellow), common allosteric (green), and cholesterol (cyan) binding sites at the M₂ receptor (4MQT) (colored in red-white-blue gradient).

Figure 3

Extracellular view of two binding centers (green) in the common allosteric binding site at the M₂ receptor (4MQT) (colored in red-white-blue gradient).

Figure 4

Structures of M₁-selective benzyl quinolone carboxylic acid (BQCA), BQZ12, M₂-selective LY2119620, and M₄-selective LY2033298 allosteric modulator.

Figure 5

Structures of M₁ allosteric modulators MIPS1674 and VU0029767.

Figure 6

Structures of bitopic ligands AC-42, 77-LH-28-1, and TBPB.

Figure 7

Scheme of isomerization of photo-switchable ligand, consisting of the orthosteric (O) and allosteric (A) moiety connected by the linker.

Figure 8

The core structure of 4-phenylpyridin-2-one derivatives.

Figure 9

Structure of M₅-selective negative allosteric modulators (NAM) of acetylcholine ML375.

Figure 10

Structure of M₃-selective positive allosteric modulators (PAM) of acetylcholine VU0119498.