scholarly journals Molecular Mechanisms of Action of M5 Muscarinic Acetylcholine Receptor Allosteric Modulators

2016 ◽  
Vol 90 (4) ◽  
pp. 427-436 ◽  
Author(s):  
Alice E. Berizzi ◽  
Patrick R. Gentry ◽  
Patricia Rueda ◽  
Sandra Den Hoedt ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Mechanisms Of Action ◽  
Allosteric Modulators ◽  
Muscarinic Acetylcholine

scholarly journals Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor

2016 ◽  
Vol 7 (5) ◽  
pp. 647-661 ◽  
Author(s):  
Shailesh N. Mistry ◽  
Herman Lim ◽  
Manuela Jörg ◽  
Ben Capuano ◽  
Arthur Christopoulos ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptor ◽  
Allosteric Modulators ◽  
Muscarinic Acetylcholine ◽  
M1 Muscarinic Acetylcholine Receptor ◽  
M1 Muscarinic

Molecular mechanism of doxorubicin-induced anticholinergic effect in guinea-pig atria

2000 ◽  
Vol 78 (6) ◽  
pp. 483-489 ◽  
Author(s):  
Yukio Hara ◽  
Kyosuke Temma ◽  
Zin Sekiya ◽  
Akihito Chugun ◽  
Hiroshi Kondo
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Acetylcholine Receptor ◽  
Action Potential Duration ◽  
Molecular Mechanisms ◽  
Muscarinic Acetylcholine Receptor ◽  
Anticholinergic Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Muscarinic Acetylcholine

The molecular mechanisms of anticholinergic actions of doxorubicin were examined by electrophysiological methods in atria and myocytes isolated from guinea-pig heart. A direct anticholinergic action of doxorubicin was confirmed with antagonistic action on carbachol-induced negative inotropic effect in atria. Both carbachol and adenosine produced shortening of action potential duration in atria measured by a microelectrode method. Doxorubicin (10-100 µM) inhibited the carbachol-induced action potential shortening in a concentration-dependent manner. However, doxorubicin did not antagonize the shortening elicited by adenosine. The whole-cell voltage clamp technique was performed to induce the muscarinic acetylcholine-receptor-operated K+ current (IK.ACh) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 µM) suppressed carbachol-induced IK.ACh in a concentration-dependent manner (IC50 = 5.6 µM). In contrast, doxorubicin (10 and 100 µM) suppressed neither adenosine-induced IK.ACh nor GTPgammaS-induced IK.ACh. These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.Key words: action potential duration, anticholinergic action, atrial cell, doxorubicin, the muscarinic acetylcholine-receptor-operated K+ current.

scholarly journals Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4)

2015 ◽  
Vol 20 (7) ◽  
pp. 858-868 ◽  
Author(s):  
Emery Smith ◽  
Peter Chase ◽  
Colleen M. Niswender ◽  
Thomas J. Utley ◽  
Douglas J. Sheffler ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptors ◽  
Response Analysis ◽  
Allosteric Modulators ◽  
Muscarinic Acetylcholine ◽  
Single Well ◽  
Well Assay ◽  
Receptor Modulators

Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer’s disease and other disorders involving impaired cognitive function. In an attempt to identify orthosteric and allosteric modulators of the muscarinic acetylcholine receptor M4 (M4), we developed a homogenous, multiparametric, 1536-well assay to measure M4 receptor agonism, positive allosteric modulation (PAM), and antagonism in a single well. This assay yielded a Z′ of 0.85 ± 0.05 in the agonist, 0.72 ± 0.07 in PAM, and 0.80 ± 0.06 in the antagonist mode. Parallel screening of the M1 and M5 subtypes using the same multiparametric assay format revealed chemotypes that demonstrate selectivity and/or promiscuity between assays and modalities. This identified 503 M4 selective primary agonists, 1450 PAMs, and 2389 antagonist hits. Concentration-response analysis identified 25 selective agonists, 4 PAMs, and 41 antagonists. This demonstrates the advantages of this approach to rapidly identify selective receptor modulators while efficiently removing assay artifacts and undesirable compounds.

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