The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice

Maninder Malik, Claudia Rangel-Barajas, Nathalie Sumien, Chang Su, Meharvan Singh, Zhenglan Chen, Ren-Qi Huang, Johann Meunier, Tangui Maurice, Robert H. Mach, Robert T. Luedtke

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background and Purpose Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory. Experimental Approach Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice given scopolamine (1 mg·kg -1 ) were used to evaluate the ability of LS-1-137, a novel sigma (σ1) receptor-selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration. Key Results LS-1-137 is a high-affinity (K i = 3.2 nM) σ1 receptor agonist that is 80-fold selective for σ1, compared with σ2 receptors. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of brain-derived neurotrophic factor from rat astrocytes. Conclusions and Implications The σ1 receptor-selective compound LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of muscarinic receptor-dependent cognitive deficits.

Original languageEnglish
Pages (from-to)2519-2531
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number10
DOIs
StatePublished - 1 May 2015

Fingerprint

Muscarinic Antagonists
Muscarinic Receptors
Ligands
Scopolamine Hydrobromide
Nootropic Agents
Aptitude
Brain-Derived Neurotrophic Factor
Memory Disorders
Dopamine Receptors
Drug Discovery
Therapeutics
Inbred C57BL Mouse
Astrocytes
Cognition
Cholinergic Agents
Parkinson Disease
sigma-1 receptor
N-(1-benzylpiperidin-4-yl)phenylacetamide
Alzheimer Disease
Stroke

Cite this

Malik, Maninder ; Rangel-Barajas, Claudia ; Sumien, Nathalie ; Su, Chang ; Singh, Meharvan ; Chen, Zhenglan ; Huang, Ren-Qi ; Meunier, Johann ; Maurice, Tangui ; Mach, Robert H. ; Luedtke, Robert T. / The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 10. pp. 2519-2531.
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The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice. / Malik, Maninder; Rangel-Barajas, Claudia; Sumien, Nathalie; Su, Chang; Singh, Meharvan; Chen, Zhenglan; Huang, Ren-Qi; Meunier, Johann; Maurice, Tangui; Mach, Robert H.; Luedtke, Robert T.

In: British Journal of Pharmacology, Vol. 172, No. 10, 01.05.2015, p. 2519-2531.

Research output: Contribution to journalArticle

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AU - Malik, Maninder

AU - Rangel-Barajas, Claudia

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AU - Su, Chang

AU - Singh, Meharvan

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AU - Luedtke, Robert T.

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