Associate editor: A. ChristopoulosMuscarinic acetylcholine receptors as CNS drug targets
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
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