In Vivo Pharmacological Comparison of TAK-071, a Positive Allosteric Modulator of Muscarinic M Receptor, and Xanomeline, an Agonist of Muscarinic M/M Receptor, in Rodents.

08:00 EDT 9th July 2019 | BioPortfolio

Summary of "In Vivo Pharmacological Comparison of TAK-071, a Positive Allosteric Modulator of Muscarinic M Receptor, and Xanomeline, an Agonist of Muscarinic M/M Receptor, in Rodents."

Activation of the M muscarinic acetylcholine receptor (MR) may be an effective therapeutic approach for Alzheimer's disease (AD), dementia with Lewy bodies, and schizophrenia. Previously, the MR/MR agonist xanomeline was shown to improve cognitive function and exert antipsychotic effects in patients with AD and schizophrenia. However, its clinical development was discontinued because of its cholinomimetic side effects. We compared in vivo pharmacological profiles of a novel MR-selective positive allosteric modulator, TAK-071, and xanomeline in rodents. Xanomeline suppressed both methamphetamine- and MK-801-induced hyperlocomotion in mice, whereas TAK-071 suppressed only MK-801-induced hyperlocomotion. In a previous study, we showed that TAK-071 improved scopolamine-induced cognitive deficits in a rat novel object recognition task (NORT) with 33-fold margins versus cholinergic side effects (diarrhea). Xanomeline also improved scopolamine-induced cognitive impairments in a NORT; however, it had no margin versus cholinergic side effects (e.g., diarrhea, salivation, and hypoactivity) in rats. These side effects were observed even in MR knockout mice. Evaluation of c-Fos expression as a marker of neural activation revealed that xanomeline increased the number of c-Fos-positive cells in several cortical areas, the hippocampal formation, amygdala, and nucleus accumbens. Other than in the orbital cortex and claustrum, TAK-071 induced similar c-Fos expression patterns. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects.


Journal Details

This article was published in the following journal.

Name: Neuroscience
ISSN: 1873-7544


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Medical and Biotech [MESH] Definitions

A specific subtype of muscarinic receptor found in the CORPUS STRIATUM and the LUNG. It has similar receptor binding specificities to MUSCARINIC RECEPTOR M1 and MUSCARINIC RECEPTOR M2.

A specific subtype of muscarinic receptor found in the lower BRAIN, the HEART and in SMOOTH MUSCLE-containing organs. Although present in smooth muscle the M2 muscarinic receptor appears not to be involved in contractile responses.

A specific subtype of muscarinic receptor that has a high affinity for the drug PIRENZEPINE. It is found in the peripheral GANGLIA where it signals a variety of physiological functions such as GASTRIC ACID secretion and BRONCHOCONSTRICTION. This subtype of muscarinic receptor is also found in neuronal tissues including the CEREBRAL CORTEX and HIPPOCAMPUS where it mediates the process of MEMORY and LEARNING.

A subclass of muscarinic receptor that mediates cholinergic-induced contraction in a variety of SMOOTH MUSCLES.

A specific subtype of muscarinic receptor found in a variety of locations including the SALIVARY GLANDS and the SUBSTANTIA NIGRA and VENTRAL TEGMENTAL AREA of the BRAIN.

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