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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.
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The delta opioid receptor (DOPr) is an emerging target for the management of chronic pain and depression. Studies have highlighted the potential of biased signaling, the preferential activation of one...
Activation of the muscarinic M1 receptor is a promising approach to improve cognitive deficits associated with cholinergic dysfunction in Alzheimer's disease, dementia with Lewy bodies, and schizophre...
The bronchodilator tiotropium is shown to not only bind to its main binding site on the M muscarinic receptor, but also to an allosteric site. In this study, we investigated the functional relevance o...
Allosteric modulators bound to structurally diverse allosteric sites can achieve better pharmacological advantages than orthosteric ligands. The discovery of allosteric modulators, however, has been t...
Discovery of an orally bioavailable and Central Nervous System (CNS) penetrant mGlu7 Negative Allosteric Modulator (NAM) in vivo tool compound: N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962).
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal ...
The purpose of this open-label, 3-part study is to investigate the safety and efficacy of [11C]MK-6884 as a Positron Emission Tomography (PET) imaging agent for quantifying muscarinic 4 (M...
The study test whether the NSAID allosteric site of human sulfotransferase 1A1 (SULT1A1) is operative in humans. The study will test the effects of mefenamic acid (MEF) on the sulfonation ...
This is an open-label study designed to evaluate the safety, tolerability and efficacy of CAD-1883, a positive allosteric modulator of the SK channel, administered twice daily orally to ad...
This study investigates the brain response to a single acute dose of AZD7325, a GABA-A positive allosteric modulator, compared to a single dose of placebo in adults with and without autism...
Insights into the pathophysiology of functional dyspepsia, with recent demonstration of inflammation with eosinophilia and mastocytosis in the duodenum (3, 6, 7), providing a possible lead...
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.
Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...
Psychiatry is the study of mental disorders and their diagnosis, management and prevention. Conditions include schizophrenia, severe depression and panic disorders among others. There are pharmaceutical treatments as well as other therapies to help...