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[PMID]:28598634
[Au] Autor:Davoren JE; Garnsey M; Pettersen B; Brodney MA; Edgerton JR; Fortin JP; Grimwood S; Harris AR; Jenkinson S; Kenakin T; Lazzaro JT; Lee CW; Lotarski SM; Nottebaum L; O'Neil SV; Popiolek M; Ramsey S; Steyn SJ; Thorn CA; Zhang L; Webb D
[Ti] Título:Design and Synthesis of γ- and δ-Lactam M Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M -Selective PAM with Weak Agonist Activity.
[So] Source:J Med Chem;60(15):6649-6663, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent data demonstrated that activation of the muscarinic M receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M and M activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M -selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M is sufficient to elicit cholinergic AEs.
[Mh] Termos MeSH primário: Isoindóis/farmacologia
Lactamas/farmacologia
Oxazóis/farmacologia
Receptor Muscarínico M1/agonistas
Convulsões/induzido quimicamente
[Mh] Termos MeSH secundário: Regulação Alostérica
Anfetamina/farmacologia
Animais
Ataxia/induzido quimicamente
Diarreia/induzido quimicamente
Cães
Desenho de Drogas
Feminino
Seres Humanos
Indanos/farmacologia
Isoindóis/administração & dosagem
Isoindóis/síntese química
Isoindóis/toxicidade
Lactamas/administração & dosagem
Lactamas/síntese química
Lactamas/toxicidade
Masculino
Camundongos Endogâmicos C57BL
Microssomos Hepáticos/metabolismo
Oxazóis/administração & dosagem
Oxazóis/síntese química
Oxazóis/toxicidade
Piperidinas/farmacologia
Ratos Wistar
Receptor Muscarínico M1/antagonistas & inibidores
Hidrobrometo de Escopolamina/farmacologia
Relação Estrutura-Atividade
Sulfonamidas/farmacologia
Tiadiazóis/farmacologia
Vômito/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indans); 0 (Isoindoles); 0 (Lactams); 0 (N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide); 0 (Oxazoles); 0 (PF-06827443); 0 (Piperidines); 0 (Receptor, Muscarinic M1); 0 (Sulfonamides); 0 (Thiadiazoles); 451IFR0GXB (Scopolamine Hydrobromide); 8SSC91326P (donepezil); CK833KGX7E (Amphetamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00597


  2 / 1194 MEDLINE  
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[PMID]:28351483
[Au] Autor:Chintamaneni PK; Krishnamurthy PT; Rao PV; Pindiprolu SS
[Ad] Endereço:Department of Pharmacology, JSS College of Pharmacy, (A Constituent of JSS University Mysore), Ootacamund, Tamil Nadu 643001, India.
[Ti] Título:Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease.
[So] Source:Med Hypotheses;101:17-22, 2017 Apr.
[Is] ISSN:1532-2777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M -M muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects.
[Mh] Termos MeSH primário: Doença de Alzheimer/terapia
Inibidores da Colinesterase/uso terapêutico
Sistemas de Liberação de Medicamentos
Nanoconjugados/química
Receptor Muscarínico M1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Acetilcolina/química
Sítio Alostérico
Animais
Barreira Hematoencefálica
Encéfalo/efeitos dos fármacos
Regulação da Expressão Gênica
Seres Humanos
Indanos/uso terapêutico
Ligantes
Lipídeos/química
Camundongos
Modelos Teóricos
Nanomedicina
Tamanho da Partícula
Fosforilação
Piperidinas/uso terapêutico
Placa Amiloide/metabolismo
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Ligands); 0 (Lipids); 0 (Nanoconjugates); 0 (Piperidines); 0 (Receptor, Muscarinic M1); 8SSC91326P (donepezil); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE


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[PMID]:28336323
[Au] Autor:Lv X; Dickerson JW; Rook JM; Lindsley CW; Conn PJ; Xiang Z
[Ad] Endereço:Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
[Ti] Título:M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.
[So] Source:Neuropharmacology;118:209-222, 2017 May 15.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M ) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
[Mh] Termos MeSH primário: Corpo Estriado/citologia
Potenciais Pós-Sinápticos Excitadores/fisiologia
Neurônios/fisiologia
Receptor Muscarínico M1/metabolismo
[Mh] Termos MeSH secundário: Acetilcolina/farmacologia
Potenciais de Ação/efeitos dos fármacos
Potenciais de Ação/genética
Animais
Channelrhodopsins
Colina O-Acetiltransferase/genética
Colina O-Acetiltransferase/metabolismo
Colinérgicos/farmacologia
Sinais (Psicologia)
Antagonistas de Aminoácidos Excitatórios/farmacologia
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Aprendizagem/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Atividade Motora/efeitos dos fármacos
Atividade Motora/genética
Neurônios/efeitos dos fármacos
Estimulação Luminosa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Channelrhodopsins); 0 (Cholinergic Agents); 0 (Excitatory Amino Acid Antagonists); 0 (Receptor, Muscarinic M1); EC 2.3.1.6 (Choline O-Acetyltransferase); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE


  4 / 1194 MEDLINE  
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[PMID]:28326934
[Au] Autor:Koga K; Matsuzaki Y; Honda K; Eto F; Furukawa T; Migita K; Irie K; Mishima K; Ueno S
[Ad] Endereço:1 Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Japan.
[Ti] Título:Activations of muscarinic M receptors in the anterior cingulate cortex contribute to the antinociceptive effect via GABAergic transmission.
[So] Source:Mol Pain;13:1744806917692330, 2017 Jan.
[Is] ISSN:1744-8069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background Cholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods. Results We found that muscarinic M receptors were clearly expressed in the anterior cingulate cortex. Using behavioral tests, we identified that microinjection of a selective muscarinic M receptors agonist McN-A-343 into the anterior cingulate cortex dose dependently increased the mechanical threshold. In contrast, the local injection of McN-A-343 into the anterior cingulate cortex showed normal motor function. The microinjection of a selective M receptors antagonist pirenzepine blocked the McN-A-343-induced antinociceptive effect. Pirenzepine alone into the anterior cingulate cortex decreased the mechanical thresholds. The local injection of the GABA receptors antagonist bicuculline into the anterior cingulate cortex also inhibited the McN-A-343-induced antinociceptive effect and decreased the mechanical threshold. Finally, we further tested whether the activation of M receptors could regulate GABAergic transmission using whole-cell patch-clamp recordings. The activation of M receptors enhanced the frequency of spontaneous and miniature inhibitory postsynaptic currents as well as the amplitude of spontaneous inhibitory postsynaptic currents in the anterior cingulate cortex. Conclusions These results suggest that the activation of muscarinic M receptors in part increased the mechanical threshold by increasing GABAergic transmitter release and facilitating GABAergic transmission in the anterior cingulate cortex.
[Mh] Termos MeSH primário: Analgésicos/uso terapêutico
Giro do Cíngulo/metabolismo
Hiperalgesia/tratamento farmacológico
Receptor Muscarínico M1/metabolismo
Transmissão Sináptica/fisiologia
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/uso terapêutico
Analgésicos/farmacologia
Animais
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia
GABAérgicos/farmacologia
Giro do Cíngulo/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/fisiologia
Masculino
Atividade Motora/efeitos dos fármacos
Atividade Motora/fisiologia
Agonistas Muscarínicos/farmacologia
Agonistas Muscarínicos/uso terapêutico
Antagonistas Muscarínicos/farmacologia
Pirenzepina/farmacologia
Ratos
Ratos Wistar
Transmissão Sináptica/efeitos dos fármacos
Ácido gama-Aminobutírico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Excitatory Amino Acid Agents); 0 (GABA Agents); 0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M1); 3G0285N20N (Pirenzepine); 55-45-8 ((4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1177/1744806917692330


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[PMID]:28137966
[Au] Autor:Radzicki D; Pollema-Mays SL; Sanz-Clemente A; Martina M
[Ad] Endereço:Department of Physiology and.
[Ti] Título:Loss of M1 Receptor Dependent Cholinergic Excitation Contributes to mPFC Deactivation in Neuropathic Pain.
[So] Source:J Neurosci;37(9):2292-2304, 2017 Mar 01.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In chronic pain, the medial prefrontal cortex (mPFC) is deactivated and mPFC-dependent tasks such as attention and working memory are impaired. We investigated the mechanisms of mPFC deactivation in the rat spared nerve injury (SNI) model of neuropathic pain. Patch-clamp recordings in acute slices showed that, 1 week after the nerve injury, cholinergic modulation of layer 5 (L5) pyramidal neurons was severely impaired. In cells from sham-operated animals, focal application of acetylcholine induced a left shift of the input/output curve and persistent firing. Both of these effects were almost completely abolished in cells from SNI-operated rats. The cause of this impairment was an ∼60% reduction of an M1-coupled, pirenzepine-sensitive depolarizing current, which appeared to be, at least in part, the consequence of M1 receptor internalization. Although no changes were detected in total M1 protein or transcript, both the fraction of the M1 receptor in the synaptic plasma membrane and the biotinylated M1 protein associated with the total plasma membrane were decreased in L5 mPFC of SNI rats. The loss of excitatory cholinergic modulation may play a critical role in mPFC deactivation in neuropathic pain and underlie the mPFC-specific cognitive deficits that are comorbid with neuropathic pain. The medial prefrontal cortex (mPFC) undergoes major reorganization in chronic pain. Deactivation of mPFC output is causally correlated with both the cognitive and the sensory component of neuropathic pain. Here, we show that cholinergic excitation of commissural layer 5 mPFC pyramidal neurons is abolished in neuropathic pain rats due to a severe reduction of a muscarinic depolarizing current and M1 receptor internalization. Therefore, in neuropathic pain rats, the acetylcholine (ACh)-dependent increase in neuronal excitability is reduced dramatically and the ACh-induced persisting firing, which is critical for working memory, is abolished. We propose that the blunted cholinergic excitability contributes to the functional mPFC deactivation that is causal for the pain phenotype and represents a cellular mechanism for the attention and memory impairments comorbid with chronic pain.
[Mh] Termos MeSH primário: Acetilcolina/metabolismo
Limiar da Dor/fisiologia
Córtex Pré-Frontal/metabolismo
Receptor Muscarínico M1/metabolismo
Ciática/patologia
[Mh] Termos MeSH secundário: Acetilcolina/farmacologia
Potenciais de Ação/efeitos dos fármacos
Animais
Modelos Animais de Doenças
Antagonistas de Aminoácidos Excitatórios/farmacologia
Antagonistas GABAérgicos/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Hiperalgesia/fisiopatologia
Masculino
Picrotoxina/farmacologia
Córtex Pré-Frontal/patologia
Córtex Pré-Frontal/ultraestrutura
Células Piramidais/efeitos dos fármacos
Células Piramidais/fisiologia
Quinoxalinas/farmacologia
Ratos
Ratos Sprague-Dawley
Receptor Muscarínico M1/genética
Ciática/fisiopatologia
Frações Subcelulares/metabolismo
Frações Subcelulares/patologia
Transmissão Sináptica/efeitos dos fármacos
Valina/análogos & derivados
Valina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Antagonists); 0 (GABA Antagonists); 0 (Quinoxalines); 0 (Receptor, Muscarinic M1); 124-87-8 (Picrotoxin); 62T278S1MX (FG 9041); 76326-31-3 (2-amino-5-phosphopentanoic acid); HG18B9YRS7 (Valine); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1553-16.2017


  6 / 1194 MEDLINE  
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[PMID]:28117571
[Au] Autor:Messerer R; Kauk M; Volpato D; Alonso Canizal MC; Klöckner J; Zabel U; Nuber S; Hoffmann C; Holzgrabe U
[Ad] Endereço:Department of Pharmaceutical and Medical Chemistry, Institute of Pharmacy, University of Würzburg , Am Hubland, 97074 Würzburg, Germany.
[Ti] Título:FRET Studies of Quinolone-Based Bitopic Ligands and Their Structural Analogues at the Muscarinic M Receptor.
[So] Source:ACS Chem Biol;12(3):833-843, 2017 Mar 17.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aiming to design partial agonists as well as allosteric modulators for the M muscarinic acetylcholine (M AChR) receptor, two different series of bipharmacophoric ligands and their structural analogues were designed and synthesized. The hybrids were composed of the benzyl quinolone carboxylic acid (BQCA)-derived subtype selective allosteric modulator 3 and the orthosteric building block 4-((4,5-dihydroisoxazol-3-yl)oxy)-N,N-dimethylbut-2-yn-1-amine (base of iperoxo) 1 or the endogenous ligand 2-(dimethylamino)ethyl acetate (base of acetylcholine) 2, respectively. The two pharmacophores were linked via alkylene chains of different lengths (C4, C6, C8, and C10). Furthermore, the corresponding structural analogues of 1 and 2 and of modified BQCA 3 with varying alkyl chain length between C2 and C10 were investigated. Fluorescence resonance energy transfer (FRET) measurements in a living single cell system were investigated in order to understand how these compounds interact with a G protein-coupled receptor (GPCR) on a molecular level and how the single moieties contribute to ligand receptor interaction. The characterization of the modified orthosteric ligands indicated that a linker attached to an orthoster rapidly attenuates the receptor response. Linker length elongation increases the receptor response of bitopic ligands, until reaching a maximum, followed by a gradual decrease. The optimal linker length was found to be six methylene groups at the M AChR. A new conformational change is described that is not of inverse agonistic origin for long linker bitopic ligands and was further investigated by exceptional fragment-based screening approaches.
[Mh] Termos MeSH primário: Quinolonas/química
Receptor Muscarínico M1/química
[Mh] Termos MeSH secundário: Transferência Ressonante de Energia de Fluorescência
Ligantes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Quinolones); 0 (Receptor, Muscarinic M1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.6b00828


  7 / 1194 MEDLINE  
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[PMID]:28094765
[Au] Autor:Calcutt NA; Smith DR; Frizzi K; Sabbir MG; Chowdhury SK; Mixcoatl-Zecuatl T; Saleh A; Muttalib N; Van der Ploeg R; Ochoa J; Gopaul A; Tessler L; Wess J; Jolivalt CG; Fernyhough P
[Ti] Título:Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy.
[So] Source:J Clin Invest;127(2):608-622, 2017 Feb 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/tratamento farmacológico
Neuropatias Diabéticas/tratamento farmacológico
Hiperalgesia/tratamento farmacológico
Antagonistas Muscarínicos/farmacologia
Receptor Muscarínico M1/antagonistas & inibidores
Células Receptoras Sensoriais/metabolismo
[Mh] Termos MeSH secundário: Animais
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Experimental/patologia
Neuropatias Diabéticas/genética
Neuropatias Diabéticas/metabolismo
Neuropatias Diabéticas/patologia
Hiperalgesia/genética
Hiperalgesia/metabolismo
Masculino
Camundongos
Camundongos Mutantes
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Neuritos/metabolismo
Neuritos/patologia
Ratos
Receptor Muscarínico M1/genética
Células Receptoras Sensoriais/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170118
[St] Status:MEDLINE


  8 / 1194 MEDLINE  
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[PMID]:28001356
[Au] Autor:Rook JM; Abe M; Cho HP; Nance KD; Luscombe VB; Adams JJ; Dickerson JW; Remke DH; Garcia-Barrantes PM; Engers DW; Engers JL; Chang S; Foster JJ; Blobaum AL; Niswender CM; Jones CK; Conn PJ; Lindsley CW
[Ad] Endereço:Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
[Ti] Título:Diverse Effects on M Signaling and Adverse Effect Liability within a Series of M Ago-PAMs.
[So] Source:ACS Chem Neurosci;8(4):866-883, 2017 Apr 19.
[Is] ISSN:1948-7193
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Both historical clinical and recent preclinical data suggest that the M muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M activation. Efforts then shifted to focus on selective activation of M via either allosteric agonists or positive allosteric modulators (PAMs). While M PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M ago-PAMs. Our data demonstrate that closely related M PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M PAMs.
[Mh] Termos MeSH primário: Regulação Alostérica/efeitos dos fármacos
Descoberta de Drogas
Agonistas Muscarínicos/química
Agonistas Muscarínicos/farmacologia
Receptor Muscarínico M1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Camundongos
Agonistas Muscarínicos/síntese química
Ratos
Receptor Muscarínico M1/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Muscarinic Agonists); 0 (Receptor, Muscarinic M1)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1021/acschemneuro.6b00429


  9 / 1194 MEDLINE  
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[PMID]:27992867
[Au] Autor:Jayasuriya GM; Elmslie G; Burstein ES; Ellis J
[Ad] Endereço:Departments of Psychiatry and Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.
[Ti] Título:Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence.
[So] Source:Pharmacology;99(3-4):128-138, 2017.
[Is] ISSN:1423-0313
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M1, M3, and M5 receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M1 and M3, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M3 receptor subtype, but does not affect the acetylcholine-stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M3, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M1 subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M3 subtype; also, NEA reverses the enhancement of pilocarpine's response at M3 produced by either dronedarone or amiodarone. In studies with the M1-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M1 subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M1 and M3 muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.
[Mh] Termos MeSH primário: Amiodarona/análogos & derivados
Receptor Muscarínico M1/agonistas
Receptor Muscarínico M1/metabolismo
Receptor Muscarínico M3/agonistas
Receptor Muscarínico M3/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Regulação Alostérica/fisiologia
Amiodarona/química
Amiodarona/metabolismo
Amiodarona/farmacologia
Animais
Células CHO
Cricetinae
Cricetulus
Relação Dose-Resposta a Droga
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Muscarinic M1); 0 (Receptor, Muscarinic M3); JQZ1L091Y2 (dronedarone); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170317
[Lr] Data última revisão:
170317
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1159/000453362


  10 / 1194 MEDLINE  
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[PMID]:27991860
[Au] Autor:Bradley SJ; Bourgognon JM; Sanger HE; Verity N; Mogg AJ; White DJ; Butcher AJ; Moreno JA; Molloy C; Macedo-Hatch T; Edwards JM; Wess J; Pawlak R; Read DJ; Sexton PM; Broad LM; Steinert JR; Mallucci GR; Christopoulos A; Felder CC; Tobin AB
[Ti] Título:M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.
[So] Source:J Clin Invest;127(2):487-499, 2017 Feb 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Hipocampo/metabolismo
Transtornos da Memória/tratamento farmacológico
Doenças Priônicas/tratamento farmacológico
Quinolinas/farmacologia
Receptor Muscarínico M1/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Regulação Alostérica/genética
Doença de Alzheimer/genética
Doença de Alzheimer/metabolismo
Doença de Alzheimer/fisiopatologia
Animais
Hipocampo/fisiopatologia
Seres Humanos
Transtornos da Memória/genética
Transtornos da Memória/metabolismo
Transtornos da Memória/fisiopatologia
Camundongos
Camundongos Knockout
Doenças Priônicas/genética
Doenças Priônicas/metabolismo
Doenças Priônicas/fisiopatologia
Receptor Muscarínico M1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid); 0 (Quinolines); 0 (Receptor, Muscarinic M1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE



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