Associate editor: A. Christopoulos
Muscarinic acetylcholine receptors as CNS drug targets

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Abstract

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the CNS where they control a variety of neuronal functions. Due to their roles in a number of CNS processes, mAChRs have long been a target of the drug discovery industry; however, the only mAChR ligands approved for use in the clinic are non-selective antagonists for the treatment of Parkinson's disease. This article briefly reviews recent progress made in mAChR drug discovery for Alzheimer's disease (AD), schizophrenia and Parkinson's disease, with particular emphasis on novel target validation, as well as highlighting novel indications such as drug addiction.

Introduction

Muscarinic acetylcholine receptors (mAChRs) are amongst the best-characterised of the seven transmembrane (7TM) receptors and are widely expressed throughout the CNS. Five mAChR subtypes have been cloned (M1, M2, M3, M4 and M5) and are generally considered to divide into two distinct classes based on signal transduction (Table 1. M1, M3 and M5 mAChR subtypes couple via Gq/11 proteins to activate phospholipase-C and mobilise intracellular calcium (Table 1). M2 and M4 mAChRs, however, predominantly signal through Gi/o proteins to inhibit adenylate cyclase and reduce the intracellular concentration of cAMP (Table 1).

The predominant mAChR in the CNS is the M1 subtype, which is located in the cortex, hippocampus, striatum and thalamus where it is found post-synaptically (Ellis, 2002). M2 mAChRs are located predominantly in the brainstem and thalamus, though also in the cortex, hippocampus and striatum where they reside on cholinergic synaptic terminals (Rouse et al., 1997) and are thought to control ACh release (Raiteri et al., 1990). M3 and M5 mAChRs are expressed at much lower levels than M1 or M2 mAChRs in the CNS, but M3 mAChRs are found in the cortex and hippocampus (Ellis, 2002) whereas M5 mAChRs have a very discrete localisation in the substantia nigra (Vilaro et al., 1990, Ellis, 2002). M4 mAChRs are found in many brain regions including the cortex and hippocampus, but are most prominent in the striatum (Ellis, 2002), where they are thought to play a role in controlling dopamine release and locomotor activity.

Given the wide and varied expression profile of the mAChRs in the CNS, it is not surprising that all of the subtypes have been evaluated as potential drug targets. Some of these targets are well accepted in the literature e.g. M1 mAChR in Alzheimer's disease, whereas others are relatively novel e.g. M5 mAChR in drug dependence and addiction. This review covers recent developments in established fields of mAChR drug discovery as well as investigating more recent indications for targeting mAChRs, including schizophrenia and drug dependence.

Section snippets

Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder (25 million people worldwide in 1998) that affects the elderly, resulting in profound memory loss and cognitive dysfunction (Fillit et al., 2002). The aetiology of the disease is complex, but is characterised by two hallmark brain sequelae: aggregates of amyloid plaques, largely composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau proteins (Selkoe, 2001). The accumulation of Aβ

Schizophrenia

Schizophrenia is a severe, debilitating condition that affects around 1% of the adult population. It generally emerges in early adulthood and impairs the sufferer's ability to recognise what is real, manage their emotions, think clearly, make judgements and communicate. Typically, patients experience a life-long pattern of acute psychotic episodes superimposed upon chronically poor psychosocial adjustment. Their symptoms are subdivided into four domains, referred to as positive (e.g.,

Parkinson's disease

Naturally occurring or synthetic compounds with anticholinergic activity were the primary mode of treatment for Parkinson's disease in the years prior to the discovery of l-DOPA and directly acting dopamine receptor agonists. As reviewed by Duvoisin (1967), although the use of these compounds was originally “based on empirical observations” there is now a large body of evidence that attributes their antidyskinetic mechanism of action to blockade of central cholinergic mechanisms. Thus, Duvoisin

Drug dependence

Although tentative evidence exists to implicate M5 mAChRs in schizophrenia (as mentioned above), there has been increased interest in the role of this mAChR subtype in the field of drug dependence and addiction. M5 mAChRs display a very discrete CNS localisation in the ventral tegmental area (VTA), a brain region known to be involved in reward and addiction (Koob et al., 1998). The mRNA is the only subtype transcript found in the VTA (Vilaro et al., 1990, Weiner et al., 1990) and infusion of M5

Conclusions

The mAChRs are one of the best-characterised subfamilies of G protein-coupled receptors and are widely expressed in the CNS. Their varied roles in controlling neuronal function mean that they represent attractive drug targets for a range of CNS disorders including AD, schizophrenia, Parkinson's disease and drug dependence. Parkinson's disease remains the only major CNS disorder for which mAChR ligands are used in the clinic, but even so the mAChR antagonists used have been superceded by

References (115)

  • J.M. Gold

    Cognitive deficits as treatment targets in schizophrenia

    Schizophr Res

    (2004)
  • M.F. Green et al.

    Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS

    Schizophr Res

    (2004)
  • F. Guillem et al.

    Are cholinergic enhancers beneficial for memory in schizophrenia? An event-related potentials (ERPs) study of rivastigmine add-on therapy in a crossover trial

    Prog Neuropsychopharmacol Biol Psychiatry

    (2006)
  • J.J. Hagan et al.

    Place navigation in rats is impaired by lesions of the medial septum and diagonal band but not nucleus basalis magnocellularis

    Behav Brain Res

    (1988)
  • R. Haring et al.

    Amyloid precursor protein secretion via muscarinic receptors: reduced desensitization using the M1-selective agonist AF102B

    Biochem Biophys Res Commun

    (1994)
  • R. Haring et al.

    NGF promotes amyloid precursor protein secretion via muscarinic receptor activation

    Biochem Biophys Res Commun

    (1995)
  • S. Hernandez-Lopez et al.

    Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis

    Neurosci

    (1994)
  • S. Kapur et al.

    From dopamine to salience to psychosis-linking biology, pharmacology and phenomenology of psychosis

    Schizophr Res

    (2005)
  • H. Karasawa et al.

    Loss of anti-cataleptic effect of scopolamine in mice lacking muscarinic acetylcholine receptor subtype 4

    Eur J Pharmacol

    (2003)
  • G.F. Koob et al.

    Neuroscience of addiction

    Neuron

    (1998)
  • C.J. Ladner et al.

    Reduced high-affinity agonist binding at the M1 muscarinic receptor in Alzheimer's disease brain: differential sensitivity to agonists and divalent cations

    Exp Neurol

    (1999)
  • M. Laruelle et al.

    Mechanism of action of antipsychotic drugs: from dopamine D2 receptor antagonism to glutamate NMDA facilitation

    Clin Ther

    (2005)
  • A.J. Mayorga et al.

    Characterization of the muscarinic receptor subtype mediating pilocarpine-induced tremulous jaw movements in rats

    Eur J Pharmacol

    (1999)
  • J.L. Muir

    Acetylcholine, aging, and Alzheimer's disease

    Pharmacol Biochem Behav

    (1997)
  • D.M. Muller et al.

    Muscarinic M1 receptor agonists increase the secretion of the amyloid precursor protein ectodomain

    Life Sci

    (1997)
  • B.P. Murphy et al.

    Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review

    Schizophr Res

    (2006)
  • S. Oddo et al.

    Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction

    Neuron

    (2003)
  • H. Pedersen et al.

    Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline

    Bioorg Med Chem

    (1999)
  • Z. Pittel et al.

    Muscarinic control of amyloid precursor protein secretion in rat cerebral cortex and cerebellum

    Brain Res

    (1996)
  • T. Rasmussen et al.

    The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance

    Schizophr Res

    (2001)
  • S.T. Rouse et al.

    Muscarinic acetylcholine receptor subtype, M2: diverse functional implications of differential synaptic localization

    Life Sci

    (1997)
  • M.H. Schubert et al.

    Galantamine improves cognition in schizophrenic patients stabilized on risperidone

    Biol Psychiatry

    (2006)
  • H.E. Shannon et al.

    Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice

    Schizophr Res

    (2000)
  • K. Shiozaki et al.

    Decrease in GTP-sensitive high affinity agonist binding of muscarinic acetylcholine receptors in autopsied brains of dementia with Lewy bodies and Alzheimer's disease

    J Neurol Sci

    (2004)
  • G. Smith

    Animal models of Alzheimer's disease: experimental cholinergic denervation

    Brain Res

    (1988)
  • S.G. Anagnostaras et al.

    Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice

    Nat Neurosci

    (2003)
  • A.S. Basile et al.

    Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia

    Proc Natl Acad Sci U S A

    (2002)
  • T.G. Beach et al.

    Cholinergic fibre loss associated with diffuse plaques in the non-demented elderly: the preclinical stage of Alzheimer's disease?

    Acta Neuropathol

    (1997)
  • W. Billard et al.

    Identification of the primary muscarinic autoreceptor subtype in rat striatum as M2 through a correlation of in vivo microdialysis and in vitro receptor binding

    J Pharmacol Exp Ther

    (1995)
  • C.D. Blaha et al.

    Modulation of dopamine efflux in the striatum following cholinergic stimulation of the substantia nigra in intact and pedunculopontine tegmental nucleus-lesioned rats

    J Neurosci

    (1993)
  • N.C. Bodick et al.

    Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease

    Arch Neurol

    (1997)
  • T.M. Bohme et al.

    Synthesis and pharmacology of benzoxazines as highly selective antagonists at M4 muscarinic receptors

    J Med Chem

    (2002)
  • A. Breier

    Developing drugs for cognitive impairment in schizophrenia

    Schizophr Bull

    (2005)
  • J.D. Buxbaum et al.

    Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid precursor protein

    Proc Natl Acad Sci U S A

    (1992)
  • F. Bymaster et al.

    Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease

    Drug Dev Res

    (1997)
  • J.W. Clader et al.

    Muscarinic receptor agonists and antagonists in the treatment of Alzheimer's disease

    Curr Pharm Des

    (2005)
  • B. Dean et al.

    The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia

    Mol Psychiatry

    (1996)
  • B. Dean et al.

    Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia

    Mol Psychiatry

    (2002)
  • R.C. Duvoisin

    Cholinergic-anticholinergic antagonism in parkinsonism

    Arch Neurol

    (1967)
  • P. Edelstein et al.

    Physostigmine and lithium response in the schizophrenias

    Am J Psychiatry

    (1981)
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