Review
Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

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Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M1 and M4) and adverse effects due to activation of peripheral mAChRs (especially M2 and M3). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M1 and M4 that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.

Introduction

Acetylcholine (ACh)-containing neurons originating in the medial septum and the diagonal band of Broca provide one of the most crucial neuromodulatory inputs to the forebrain in humans and other mammals [1]. These cholinergic projections make synaptic contact with widespread but highly specific targets in a variety of forebrain regions including the basal ganglia, cortex and hippocampus. In addition, there are several other crucial cholinergic systems in the central nervous system (CNS) including cholinergic interneurons in the striatum, nucleus accumbens, olfactory tubercle and Islands of Calleja, in addition to cholinergic projection neurons in the substantia innominata, magnocellular preoptic field and nucleus basalis 1, 2, 3, 4. These nuclei send projections throughout the neocortex and limbic areas and have a crucial role in information processing and multiple forms of learning and memory 3, 5, 6. In addition, cholinergic projections have been implicated in a variety of other CNS functions including nociception, regulation of sleep–wake cycles, motor control and arousal. Based on this broad influence of cholinergic pathways in the CNS, agents that regulate cholinergic transmission have been proposed to have potential efficacy in a wide variety of CNS disorders including chronic and neuropathic pain, sleep disorders, epilepsy, schizophrenia, Alzheimer's disease (AD), Parkinson's disease and other movement disorders 5, 6, 7, 8, 9.

Section snippets

Therapeutic potential of M1 for the treatment of AD

Based on the broad influence of cholinergic systems in the CNS, it is surprising that there have not been greater advances in the development of therapeutic agents that target cholinergic signaling. Efforts to develop agents that enhance cholinergic transmission for ameliorating the loss of cognitive function in patients with AD and other memory disorders have been partially successful, and clinical trials with tacrine and other acetylcholinesterase (AChE) inhibitors have established

Discovery of subtype-selective allosteric modulators of mAChRs

Previous attempts to develop agonists that are highly selective for individual mAChR subtypes have failed because of the high conservation of the orthosteric ACh-binding site and difficulty developing compounds that are truly subtype specific. Although there have been reports of subtype-selective M1 agonists in the patent and primary literature, subsequent studies across multiple systems revealed that previous orthosteric agonists are not highly selective when evaluated across multiple systems.

Discovery of highly selective and systemically active M1 PAMs

Over the past two years, several novel selective M1 agonists and allosteric potentiators have been identified. These compounds are providing important new tools to evaluate the potential utility of selective activators of M1 for treatment of AD and other CNS disorders. For instance, TBPB (structure 7; Figure 3) 12, 22, 23 and 77-LH-28-1 (structure 8; Figure 3) 24, 25 have been reported as highly selective agonists of M1 relative to other mAChR subtypes (Figure 3). Both of these compounds are

Allosteric modulators of mAChRs have efficacy as novel antipsychotic agents

Of the orthosteric mAChR agonists that have been developed in clinical trials for the treatment of AD, an M1/M4 agonist termed xanomeline advanced furthest in clinical development 34, 35. Although potential cognition-enhancing effects of this compound in Phase III trials were encouraging, the most surprising finding in the xanomeline trial was that this M1/M4 agonist had robust therapeutic effects on psychotic symptoms and behavioral disturbances associated with AD 34, 35. Xanomeline induced

Conclusions

Exciting new data from animal and clinical studies indicate that ligands at mAChR subtypes might provide a novel approach to the treatment of multiple CNS disorders. This includes compelling evidence that selective increases in the activity of M1 and M4 could provide a novel approach to the treatment of AD and schizophrenia and perhaps have efficacy in treating psychosis and cognitive impairment in other neurodegenerative diseases. Major advances have been made in establishing selective

Conflict-of-interest statement

P.J.C. has received compensation over the past two years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Invitrogen Life Technologies, Evotec Inc., Addex Pharmaceuticals, Michael J. Fox Foundation, Seaside Therapeutics, Cephalon Inc., AstraZeneca USA, NeurOp Inc., Forest Research Institute, LEK Consulting, The Frankel Group, Prestwick Chemical Co., Millipore Corp., Genentech, IMS Health, Primary Insight

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