Activation of M₁ and M₄ muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia

Figures & data

Table 1 Antipsychotic and pro-cognitive effects of M₁ and M₄ selective modulators

Receptor	Mode of action	Ligand	In vivo efficacy	Species
M1	Agonist	AC-260584	Increased retention of platform location in Morris water maze^Citation56	Mouse
			Increased novel object recognition^Citation54	Mouse
		77-LH-28-1	Increased hippocampal cell firing^Citation55	Rat
		TBPB	Reversed amphetamine-induced hyperlocomotion^Citation58	Rat
			Reversed apomorphine-induced disruption of prepulse inhibition^Citation59	Rat
			Reversed amphetamine-induced disruption of cued fear conditioning^Citation59	Rat
		VU0357017	Reversed scopolamine-induced disruption of contextual fear conditioning^Citation61	Rat
			Enhanced acquisition of contextual fear^Citation60	Rat
		VU0364572	Enhanced spatial learning in Morris water maze^Citation60	Rat
			Enhanced acquisition of contextual fear^Citation60	Rat
		GSK1034702	Reversed nicotine abstinence-induced impairment of episodic memory^Citation67	Human
	PAM	BQCA	Reversed scopolamine-induced disruption of contextual fear conditioning^Citation68	Mouse
			Increased wakefulness and inhibited delta sleep^Citation68	Rat
			Enhanced cerebral blood flow^Citation68	Rat
			Decreased deficits in reversal learning in Tg2576 mice (AD model)^Citation69	Mouse
			Increased mPFC neuronal firing^Citation69	Rat
			Reversed time-induced disruption of Y-maze object recognition^Citation72	Rat
			Reversed scopolamine-induced memory deficit in spontaneous alternation task^Citation71	Rat
M1/M4	Agonist	Xanomeline	Decreased behavioral disturbances^Citation38,Citation39	Human
M4	PAM	VU0152099	Reversed amphetamine-induced hyperlocomotion^Citation86	Rat
		VU0152100	Reversed amphetamine-induced hyperlocomotion^Citation86	Rat
		LY2033298	Reversed apomorphine-induced disruption of prepulse inhibition of the acoustic startle reflex^Citation84	Rat
			Decreased conditioned avoidance responding^Citation84	Rat
			Decreased conditioned avoidance responding^Citation87	Mouse
			Reversed amphetamine-induced hyperlocomotion^Citation88	Mouse

Abbreviations: AD, Alzheimer’s disease; BQCA, benzyl quinolone carboxylic acid; mPFC, medial prefrontal cortex; M₁, muscarinic acetylcholine receptor subtype 1; M₄, muscarinic acetylcholine receptor subtype 4; PAM, positive allosteric modulator; TBPB, 1-(1’-(2-methylbenzyl)-1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1.

VanoverKEVeinbergsIDavisREAntipsychotic-like behavioral effects and cognitive enhancement by a potent and selective muscarinic M-sub-1 receptor agonist, AC-260584Behav Neurosci2008122357057518513127

 PubMed Web of Science ®Google Scholar

BradleySRLamehJOhrmundLAC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal modelNeuropharmacology201058236537319835892

 PubMed Web of Science ®Google Scholar

LangmeadCJAustinNEBranchCLCharacterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1Br J Pharmacol200815451104111518454168

 PubMed Web of Science ®Google Scholar

JonesCKBradyAEDavisAANovel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in ratsJ Neurosci20082841104221043318842902

 PubMed Web of Science ®Google Scholar

KaneAThe In Vivo Characterization of TBPB, a Novel Allosteric Agonist of M1 Muscarinic Receptors: Implications for the Role of the M1 Muscarinic Receptor in Treatment of Schizophrenia [undergraduate thesis]Nashville (TN)Vanderbilt University2008

 Google Scholar

LeboisEPBridgesTMLewisLMDiscovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous systemACS Chem Neurosci20101210412121961051

 PubMed Web of Science ®Google Scholar

DigbyGJNoetzelMJBubserMNovel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal modelsJ Neurosci201232258532854422723693

 PubMed Web of Science ®Google Scholar

NathanPJWatsonJLundJThe potent M(1) receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunctionInt J Neuropsychopharmacol201316472173122932339

 PubMed Web of Science ®Google Scholar

MaLSeagerMAWittmannMSelective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiationProc Natl Acad Sci U S A200910637159501595519717450

 PubMed Web of Science ®Google Scholar

ShireyJKBradyAEJonesPJA selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learningJ Neurosci20092945142711428619906975

 PubMed Web of Science ®Google Scholar

ChambonCWegenerNGraviusADanyszWA new automated method to assess the rat recognition memory: validation of the methodBehav Brain Res2011222115115721421012

 PubMed Web of Science ®Google Scholar

ChambonCJatzkeCWegenerNGraviusADanyszWUsing cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communicationEur J Pharmacol20126971–3738023085025

 PubMed Web of Science ®Google Scholar

BodickNCOffenWWLeveyAIEffects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer diseaseArch Neurol19975444654739109749

 PubMed Web of Science ®Google Scholar

BodickNCOffenWWShannonHEThe selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer diseaseAlzheimer Dis Assoc Disord199711 Suppl 4S16S229339268

 PubMed Web of Science ®Google Scholar

BradyAEJonesCKBridgesTMCentrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in ratsJ Pharmacol Exp Ther2008327394195318772318

 PubMed Web of Science ®Google Scholar

ChanWYMcKinzieDLBoseSAllosteric modulation of the muscarinic M4 receptor as an approach to treating schizophreniaProc Natl Acad Sci U S A200810531109781098318678919

 PubMed Web of Science ®Google Scholar

LeachKLoiaconoREFelderCCMolecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic propertiesNeuropsychopharmacology201035485586919940843

 PubMed Web of Science ®Google Scholar

SuratmanSLeachKSextonPFelderCLoiaconoRChristopoulosAImpact of species variability and ‘probe-dependence’ on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptorBr J Pharmacol201116271659167021198541

 PubMed Web of Science ®Google Scholar