المؤلفون: Abd‐Elrahman, Khaled S.^1,2,3 (AUTHOR) kshabdel@ucalgary.ca, Sarasija, Shaarika^1,2 (AUTHOR), Colson, Tash‐Lynn L.^1,2 (AUTHOR), Ferguson, Stephen S. G.^1,2 (AUTHOR) sferguso@uottawa.ca

المصدر: British Journal of Pharmacology. Apr2022, Vol. 179 Issue 8, p1769-1783. 15p. 1 Color Photograph, 1 Diagram, 4 Graphs.

مصطلحات موضوعية: *MUSCARINIC receptors, *MUSCARINIC acetylcholine receptors, *AMYLOID beta-protein precursor, *MICE, *COGNITIVE ability, *ALZHEIMER'S disease, *NEURODEGENERATION

مستخلص: Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. β‐Amyloid (Aβ) oligomers are considered the principal neurotoxic species in AD brains. The M1 muscarinic ACh receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro‐cognitive activity but cause many adverse off‐target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease‐modifying efficacy in female AD mice. Experimental Approach Nine‐month‐old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg·kg−1·day−1) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment. Key Results: VU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in Aβ oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced Aβ oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non‐amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of β‐secretase 1 (BACE1), whereas it enhanced the expression of the α‐secretase ADAM10 in APPswe hippocampus. Conclusion and Implications: Using M1 mAChR PAMs can be a viable disease‐modifying approach that should be exploited clinically to slow AD in women. [ABSTRACT FROM AUTHOR]

المؤلفون: Walker, Leigh C.^1,2 (AUTHOR) leigh.walker@florey.edu.au, Huckstep, Kate L.^1,2 (AUTHOR), Chen, Nicola A.^1,2 (AUTHOR), Hand, Lexi J.^1,2 (AUTHOR), Lindsley, Craig W.³ (AUTHOR), Langmead, Christopher J.⁴ (AUTHOR), Lawrence, Andrew J.^1,2 (AUTHOR) andrew.lawrence@florey.edu.au

المصدر: British Journal of Pharmacology. Sep2021, Vol. 178 Issue 18, p3730-3746. 17p. 6 Diagrams, 1 Chart, 1 Graph.

مصطلحات موضوعية: *LABORATORY rats, *MUSCARINIC receptors, *MUSCARINIC acetylcholine receptors, *HIPPOCAMPUS (Brain), *ALCOHOL, *ALCOHOL drinking, *TEMPERANCE

مستخلص: Background and Purpose: Muscarinic acetylcholine receptors mediate alcohol consumption and seeking in rats. While M4 and M5 receptors have recently been implicated to mediate these behaviours in the striatum, their role in other brain regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 receptors and modulate alcohol‐seeking, via their projections to the nucleus accumbens shell (AcbSh). Experimental Approach In Indiana alcohol‐preferring (iP) male rats, we examined Chrm4 (M4) and Chrm5 (M5) expression in the VTA and vSub following long‐term alcohol consumption and abstinence using RT‐qPCR. Using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M4 and M5 receptors within the vSub in alcohol consumption, context‐induced alcohol‐seeking, locomotor activity, and food/water consumption. Key Results: Long‐term alcohol and abstinence dysregulated the expression of genes for muscarinic receptors in the vSub, not in the VTA. Chrm4 was down‐regulated following long‐term alcohol and abstinence, while Chrm5 was up‐regulated following long‐term alcohol consumption. Consistent with these data, a positive allosteric modulator (VU0467154) of intra‐vSub M4 receptors reduced context‐induced alcohol‐seeking, but not motivation for alcohol self‐administration, while M5 receptor negative allosteric modulator (ML375) reduced initial motivation for alcohol self‐administration, but not context‐induced alcohol‐seeking. Conclusion and Implications: Collectively, our data highlight alcohol‐induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 receptor allosteric modulators to reduce alcohol consumption or seeking. [ABSTRACT FROM AUTHOR]

المؤلفون: Randáková, Alena¹ (AUTHOR), Nelic, Dominik¹ (AUTHOR), Ungerová, Dana¹ (AUTHOR), Nwokoye, Peter² (AUTHOR), Su, Qiwen² (AUTHOR), Doležal, Vladimír¹ (AUTHOR), El‐Fakahany, Esam E.³ (AUTHOR), Boulos, John² (AUTHOR), Jakubík, Jan¹ (AUTHOR) jan.jakubik@fgu.cas.cz, El-Fakahany, Esam E⁴ (AUTHOR)

المصدر: British Journal of Pharmacology. May2020, Vol. 177 Issue 9, p2073-2089. 17p. 2 Color Photographs, 1 Chart, 8 Graphs.

مصطلحات موضوعية: *MUSCARINIC acetylcholine receptors, *MUSCARINIC receptors, *CHOLINERGIC receptors, *MUSCARINIC agonists, *PHOSPHOLIPASE C, *CHO cell, *INOSITOL phosphates, *ANTIPYRETICS, *HAMSTERS, *RODENTS, *RESEARCH, *ANIMAL experimentation, *RESEARCH methodology, *CELL receptors, *MEDICAL cooperation, *EVALUATION research, *CELLULAR signal transduction, *RATS, *COMPARATIVE studies, *RESEARCH funding, *MUSCARINIC antagonists, *PHARMACODYNAMICS

مستخلص: Background and Purpose: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects.Experimental Approach: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M2 receptors was modelled in silico.Key Results: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor.Conclusions and Implications: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway. [ABSTRACT FROM AUTHOR]

المؤلفون: Broad, Lisa M¹ broad_lisa@lilly.com, Sanger, Helen E¹, Mogg, Adrian J¹, Colvin, Ellen M¹, Zwart, Ruud¹, Evans, David A¹, Pasqui, Francesca¹, Sher, Emanuele¹, Wishart, Graham N¹, Barth, Vanessa N², Felder, Christian C², Goldsmith, Paul J¹

المصدر: British Journal of Pharmacology. Jan2019, Vol. 176 Issue 1, p110-126. 17p. 2 Diagrams, 3 Charts, 8 Graphs.

مصطلحات موضوعية: *ALZHEIMER'S disease treatment, *MUSCARINIC receptors, *MUSCARINIC agonists, *PHARMACOLOGY, *LABORATORY rats

مستخلص: Background and Purpose: We aimed to identify and develop novel, selective muscarinic M1 receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. Experimental Approach We developed and utilized a novel M1 receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat–human) benchmarking of structure–activity relationship molecules to clinical comparators. Key Results: Using this paradigm, we identified a series of M1 receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 receptor anti‐targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose‐dependently occupies rodent cortical M1 receptors. Conclusions and Implications: We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M1 receptors in physiology and disease. [ABSTRACT FROM AUTHOR]

المؤلفون: Yoo, Edwin J, Cao, Gaoyuan, Koziol‐White, Cynthia J, Ojiaku, Christie A, Sunder, Krishna, Jude, Joseph A, Michael, James V, Lam, Hong, Pushkarsky, Ivan, Damoiseaux, Robert, Di Carlo, Dino, Ahn, Kwangmi, An, Steven S, Penn, Raymond B, Panettieri, Reynold A

المصدر: British Journal of Pharmacology. 174(23)

مصطلحات موضوعية: Medical Physiology, Biomedical and Clinical Sciences, Asthma, Lung, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Airway Obstruction, Carbachol, Cells, Cultured, GTP-Binding Protein alpha Subunits, G12-G13, Gene Knockdown Techniques, Humans, Muscle Contraction, Muscle, Smooth, Myosin Light Chains, Phosphatidylinositol 3-Kinase, Phosphorylation, Receptor, Muscarinic M3, Signal Transduction, rhoA GTP-Binding Protein, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: Background and purposePI3K-dependent activation of Rho kinase (ROCK) is necessary for agonist-induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The mechanisms driving agonist-mediated PI3K/ROCK axis activation, however, remain unclear. Given that G12 family proteins activate ROCK pathways in other cell types, their role in M3 muscarinic acetylcholine receptor-stimulated PI3K/ROCK activation and contraction was examined.Experimental approachGα12 coupling was evaluated using co-immunoprecipitation and serum response element (SRE)-luciferase reporter assays. siRNA and pharmacological approaches, as well as overexpression of a regulator of G-protein signaling (RGS) proteins were applied in HASMCs. Phosphorylation levels of Akt, myosin phosphatase targeting subunit-1 (MYPT1), and myosin light chain-20 (MLC) were measured. Contraction and shortening were evaluated using magnetic twisting cytometry (MTC) and micro-pattern deformation, respectively. Human precision-cut lung slices (hPCLS) were utilized to evaluate bronchoconstriction.Key resultsKnockdown of M3 receptors or Gα12 attenuated activation of Akt, MYPT1, and MLC phosphorylation. Gα12 coimmunoprecipitated with M3 receptors, and p115RhoGEF-RGS overexpression inhibited carbachol-mediated induction of SRE-luciferase reporter. p115RhoGEF-RGS overexpression inhibited carbachol-induced activation of Akt, HASMC contraction, and shortening. Moreover, inhibition of RhoA blunted activation of PI3K. Lastly, RhoA inhibitors induced dilation of hPCLS.Conclusions and implicationsGα12 plays a crucial role in HASMC contraction via RhoA-dependent activation of the PI3K/ROCK axis. Inhibition of RhoA activation induces bronchodilation in hPCLS, and targeting Gα12 signaling may elucidate novel therapeutic targets in asthma. These findings provide alternative approaches to the clinical management of airway obstruction in asthma.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5zv865vwTest

المؤلفون: Civciristov, Srgjan¹ (AUTHOR), Halls, Michelle L.¹ (AUTHOR) michelle.halls@monash.edu

المصدر: British Journal of Pharmacology. Jul2019, Vol. 176 Issue 14, p2382-2401. 20p. 5 Charts, 2 Graphs.

مصطلحات موضوعية: *MUSCARINIC receptors, *CHEMOTAXIS, *PROTEIN receptors, *MUSCLE contraction, *ADRENERGIC receptors, *GEOGRAPHIC boundaries

مستخلص: There is evidence for ultra-sensitive responses to active compounds at concentrations below picomolar levels by proteins and receptors found in species ranging from bacteria to mammals. We have recently shown that such ultra-sensitivity is also demonstrated by a wide range of prototypical GPCRs, and we have determined the molecular mechanisms behind these responses for three family A GPCRs: the relaxin receptor, RXFP1; the β2 -adrenoceptor; and the M3 muscarinic ACh receptor. Interestingly, there are reports of similar ultra-sensitivity by more than 15 human GPCR families, in addition to other human receptors and channels. These occur through a diverse range of signalling pathways and produce modulation of important physiological processes, including neuronal transmission, chemotaxis, gene transcription, protein/ion uptake and secretion, muscle contraction and relaxation, and phagocytosis. Here, we summarise the accumulating evidence of ultra-sensitive receptor signalling to show that this is a common, though currently underappreciated, property of GPCRs. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetocTest. [ABSTRACT FROM AUTHOR]

المؤلفون: Pulakazhi Venu, Vivek Krishna^1,2 vivek.pulakazhivenu@ucalgary.ca, Saifeddine, Mahmoud¹, Mihara, Koichiro¹, El‐Daly, Mahmoud^1,3, Belke, Darrell², Dean, Jonathan L E⁴, O'Brien, Edward R², Hirota, Simon A¹, Hollenberg, Morley D^1,5 mhollenb@ucalgary.ca, El-Daly, Mahmoud^6,7 (AUTHOR)

المصدر: British Journal of Pharmacology. Jun2018, Vol. 175 Issue 11, p2063-2076. 14p. 6 Graphs.

مصطلحات موضوعية: *HEAT shock proteins, *MUSCARINIC receptors, *PROTEINASES, *ENDOTHELIAL cells, *MESSENGER RNA

مستخلص: Background and Purpose: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2).Experimental Approach: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice.Key Results: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1.Conclusions and Implications: HSPB1 can regulate intact vascular endothelial function to affect NO-mediated vascular relaxation, especially in females. [ABSTRACT FROM AUTHOR]

المؤلفون: Randáková, Alena¹, Rudajev, Vladimír¹, Doležal, Vladimír¹, Boulos, John², Jakubík, Jan¹ jan.jakubik@fgu.cas.cz

المصدر: British Journal of Pharmacology. May2018, Vol. 175 Issue 10, p1731-1743. 13p. 2 Diagrams, 6 Charts, 14 Graphs.

مصطلحات موضوعية: *MUSCARINIC receptors, *CHOLINERGIC receptors, *MENTAL illness, *PARASYMPATHOMIMETIC agents, *CARBACHOL

مستخلص: Background and Purpose: The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects.Experimental Approach: The binding and antagonism of functional responses to the agonist carbachol mediated by 4-hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues.Key Results: The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M1 to 4 μM at M3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors.Conclusions and Implications: The 4-hexyloxy derivatives were found to be potent long-acting M1 -preferring antagonists. In view of current literature, M1 -selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits. [ABSTRACT FROM AUTHOR]

المؤلفون: Thomson, Kate, Kelly, Tamsin, Karouta, Cindy, Morgan, Ian, Ashby, Regan

المصدر: British Journal of Pharmacology; Nov2021, Vol. 178 Issue 22, p4501-4517, 17p, 6 Charts, 4 Graphs

مصطلحات موضوعية: CARBACHOL, ATROPINE, DOPAMINE, MUSCARINIC receptors, NICOTINIC agonists, MYOPIA, NICOTINE, DOPAMINE antagonists, HYPERACTIVITY

مستخلص: Background and Purpose: The ability of the muscarinic cholinergic antagonist atropine to inhibit myopia development in humans and animal models would suggest that cholinergic hyperactivity may underlie myopic growth. To test this, we investigated whether cholinergic agonists accelerate ocular growth rates in chickens. Furthermore, we investigated whether atropine alters ocular growth by downstream modulation of dopamine levels, a mechanism postulated to underlie its antimyopic effects. Experimental Approach Muscarinic (muscarine and pilocarpine), nicotinic (nicotine) and non‐specific (oxotremorine and carbachol) cholinergic agonists were administered to chicks developing form‐deprivation myopia (FDM) or chicks that were otherwise untreated. Vitreal levels of dopamine and its primary metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) were examined using mass spectrometry MS in form‐deprived chicks treated with atropine (360, 15 or 0.15 nmol). Further, we investigated whether dopamine antagonists block atropine's antimyopic effects. Key Results: Unexpectedly, administration of each cholinergic agonist inhibited FDM but did not affect normal ocular development. Atropine only affected dopamine and DOPAC levels at its highest dose. Dopamine antagonists did not alter the antimyopia effects of atropine. Conclusion and Implications: Muscarinic, nicotinic and non‐specific cholinergic agonists inhibited FDM development. This indicates that cholinergic hyperactivity does not underlie myopic growth and questions whether atropine inhibits myopia via cholinergic antagonism. This study also demonstrates that changes in retinal dopamine release are not required for atropine's antimyopic effects. Finally, nicotinic agonists may represent a novel and more targeted approach for the cholinergic control of myopia as they are unlikely to cause the anterior segment side effects associated with muscarinic treatment. [ABSTRACT FROM AUTHOR]

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المؤلفون: Bader, Sandra¹, Lottig, Lena¹, Diener, Martin¹ martin.diener@vetmed.uni‐giessen.de

المصدر: British Journal of Pharmacology. May2017, Vol. 174 Issue 9, p880-892. 13p.

مصطلحات موضوعية: *ACETYLCHOLINE, *MUSCARINIC receptors, *NICOTINIC receptors, *CHOLINERGIC mechanisms, *ION transport (Biology), *PHARMACOLOGY, *NICOTINE metabolism, *ADENOSINE triphosphatase, *CHOLINERGIC receptors, *ANIMAL experimentation, *COLON (Anatomy), *DOSE-effect relationship in pharmacology, *EPITHELIUM, *RESEARCH methodology, *MEMBRANE proteins, *NICOTINE, *RATS, *TISSUE culture, *SODIUM channel blockers, *CHEMICAL inhibitors, *PHARMACODYNAMICS, *PHYSIOLOGY

مستخلص: Background and Purpose: Acetylcholine-induced epithelial Cl- secretion is generally thought to be mediated by epithelial muscarinic receptors and nicotinic receptors on secretomotor neurons. However, recent data have shown expression of nicotinic receptors by intestinal epithelium and the stimulation of Cl- secretion by nicotine, in the presence of the neurotoxin, tetrodotoxin. Here, we aimed to identify the transporters activated by epithelial nicotinic receptors and to clarify their role in cholinergic regulation of intestinal ion transport.Experimental Approach: Ussing chamber experiments were performed, using rat distal colon with intact epithelia. Epithelia were basolaterally depolarized to measure currents across the apical membrane. Apically permeabilized tissue was also used to measure currents across the basolateral membrane in the presence of tetrodotoxin.Key Results: Nicotine had no effect on currents through Cl- channels in the apical membrane or on currents through K+ channels in the apical or the basolateral membrane. Instead, nicotine stimulated the Na+ -K+ -pump as indicated by Na+ -dependency and sensitivity of the nicotine-induced current across the basolateral membrane to cardiac steroids. Effects of nicotine were inhibited by nicotinic receptor antagonists such as hexamethonium and mimicked by dimethyl-4-phenylpiperazinium, a chemically different nicotinic agonist. Simultaneous stimulation of epithelial muscarinic and nicotinic receptors led to a strong potentiation of transepithelial Cl- secretion.Conclusions and Implications: These results suggest a novel concept for the cholinergic regulation of transepithelial ion transport by costimulation of muscarinic and nicotinic epithelial receptors and a unique role of nicotinic receptors controlling the activity of the Na+ -K+ -ATPase. [ABSTRACT FROM AUTHOR]