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

Shannon, Harlan E.; Rasmussen, Kurt; Bymaster, Frank P.; Hart, John C.; Peters, Steven; Swedberg, Michael D.B.; Jeppesen, Lone; Sheardown, Malcolm J.; Sauerberg, Per; Fink-Jensen, Anders

doi:10.1016/s0920-9964(99)00138-3

Cited by 140 publications

(126 citation statements)

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“…In addition to validating the therapeutic utility of M 1 mAChR targeting, xanomeline also validated M 4 mAChR activation as a potential treatment for psychosis, demonstrating in vivo efficacy in both animal 18 and human 19 clinical trials, and exhibiting a similar therapeutic profile to the atypical antipsychotics clozapine and olanzapine. 15 The attenuation of amphetamineinduced psychotic behaviors observed with administration of xanomeline was absent in M 4 mAChR KO mice (but remained present in M 1 mAChR KOs).…”

Section: ■ the Cholinergic Hypothesis Of Memory Dysfunctionmentioning

confidence: 89%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M 1 muscarinic acetylcholine receptor (M 1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M 1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M 1 mAChR, comprehensively summarize and critically evaluate the M 1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. KEYWORDS: M 1 mAChR, allosteric ligands, Alzheimer's disease, schizophrenia, cognitive deficits, memory T he muscarinic acetylcholine receptor (mAChR) family is a group of rhodopsin-like (Family A) G protein-coupled receptors (GPCRs) consisting of five distinct subtypes M 1 −M 5 . Activation of the M 1 , M 3 , and M 5 receptor subtypes primarily results in coupling to the G q/11 family of G proteins, activation of phospholipase C (PLC), release of inositol-1,4,5-trisphosphate (IP 3 ), and subsequent mobilization of intracellular calcium Ca 2+ . Activation of the M 2 and M 4 receptor subtypes primarily results in coupling to the G i/o family of G proteins, inhibition of adenylate cyclase (AC), reduction in cyclic AMP (cAMP), and a decrease in neurotransmitter release via the blockage of voltage-gated calcium channels (Figure 1). These pathways represent a generalized view of each receptor's coupling capacity, as all five subtypes couple to a broader range of G protein-and non-G protein-mediated signaling and regulatory pathways, 1 ultimately leading to the regulation of enzymes and neurotransmitters critical for intercellular chemical communication and biological function. In a ...

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Section: ■ the Cholinergic Hypothesis Of Memory Dysfunctionmentioning

confidence: 89%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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“…M 1 receptor agonists have been reported to improve working memory in animals (Aura et al 1997;McDonald et al 1998) and xanomeline, a M 1 receptor agonist with minimal M 2 receptor blockade Shannon et al 1994Shannon et al , 2000, has also improved cognition, and decreased hallucinatory and delusional symptoms in Alzheimer's disease (Bodick et al 1997;Bymaster et al 1997) and perhaps schizophrenia, whereas M 1 receptor antagonists may worsen working memory in patients with schizophrenia (McEvoy 1987;Spohn and Strauss 1989;King 1990) and in animals (Bymaster et al 1993;Aura et al 1997;Roldan et al 1997). The atypical APD-induced cortical ACh release would be expected to increase M 1 receptor stimulation by diminishing M 1 receptor antagonism where it exists.…”

Section: Discussionmentioning

confidence: 99%

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Ichikawa

2002

Neuropsychopharmacology

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The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, (Perry et al. 1999) and working memory (Winkler et al. 1995), and thus, may be important to either the cognitive dysfunction of schizophrenia or the ability of antipsychotic drugs (APDs) to improve some or all aspects of that cognitive deficit (Meltzer and McGurk 1999). The atypical APDs, clozapine, olanzapine, risperidone, and quetiapine, have, in fact, been reported to improve some domains of cognitive dysfunction (see Meltzer and McGurk 1999; Purdon 1999 for reviews), in addition to psychopathology (Leucht et al. 1999) in schizophrenia, more so than typical APDs, e.g., haloperidol and phenothiazines. The basis for these advantages is unclear.The atypical APDs share in common a relatively more potent antagonist action at serotonin (5-HT) 2A NO . 3 al. 1989;Schotte et al. 1996) and ␣ 1 -and ␣ 2 -adrenoceptors (Hertel et al. 1999). These features have been related to their ability to increase DA release in the mPFC (Hertel et al. 1999; Kuroki et al. 1999; Ichikawa et al. 2001). However, a possible role for ACh in mediating these effects is receiving increasing attention. Clozapine and olanzapine, but not risperidone, quetiapine, ziprasidone, or iloperidone (Schotte et al. 1996;Bymaster et al. 1999), have significant direct agonist or antagonist effects upon various subtypes of muscarinic ACh receptors (mAChRs) (Tandon 1999), whereas the typical APDs, thioridazine and mesoridazine, are also potent mAChR antagonists (Niedzwiecki et al. 1989a,b;Bolden et al. 1992). Furthermore, trihexyphenidyl and biperiden (Bolden et al. 1992), mAChR antagonists which reduce typical APD-induced extrapyramidal symptoms (EPS), have been reported to cause complex clinical effects in patients with schizophrenia, e.g., working memory impairment (King 1990) and worsening of psychosis while decreasing negative symptoms (Tandon et al. 1992). It is possible that clozapine and olanzapine influence clinical symptoms in schizophrenia via a direct effect upon main cholinergic transmission (Zorn et al. 1994; Bymaster et al. 1996).As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al. 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al. 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key ...

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“…Xanomeline inhibited apomorphine-induced climbing, dopamine agonist-induced rotation, and dopamine cell firing in the ventral tegmental area (Shannon et al, 2000). Xanomeline also inhibited conditioned avoidance responding (Shannon et al, 2000), a traditional preclinical test used to predict antipsychotic activity (Arnt, 1982;Arnt et al, 1982). Furthermore, similar to the effects of the antipsychotic compounds clozapine and olanzapine, xanomeline increased extracellular levels of dopamine and immediateearly gene expression, that is, Fos, in the rat prefrontal cortex (Perry et al, 2001).…”

Section: Introductionmentioning

confidence: 92%

“…Recently, it was found that xanomeline, a muscarinic M 1 /M 4 preferring receptor agonist, exhibits functional dopamine antagonism in rodents despite its lack of affinity for the dopamine transporter and dopamine receptors. Xanomeline inhibited apomorphine-induced climbing, dopamine agonist-induced rotation, and dopamine cell firing in the ventral tegmental area (Shannon et al, 2000). Xanomeline also inhibited conditioned avoidance responding (Shannon et al, 2000), a traditional preclinical test used to predict antipsychotic activity (Arnt, 1982;Arnt et al, 1982).…”

Section: Introductionmentioning

confidence: 98%

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Andersen

Fink-Jensen

Peacock

et al. 2003

Neuropsychopharmacol

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Xanomeline is a muscarinic M 1 /M 4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (À)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits Damphetamine-and (À)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.

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

Cited by 140 publications

References 31 publications

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

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

Cited by 140 publications

References 31 publications

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

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Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits