Muscarinic Receptor Subtypes

Hulme, Edward C.

doi:10.1146/annurev.pharmtox.30.1.633

Cited by 161 publications

(177 citation statements)

References 0 publications

Supporting

Mentioning

167

Contrasting

Order By: Relevance

“…[1][2][3][4] Five muscarinic mAChR subtypes, M 1 -M 5 , are known to date. 2-4 M 1 -M 5 mAChRs are widely distributed in mammalian organs and the central and peripheral nerve system where they mediate important neuronal and autocrine functions including memory and attention mechanisms, motor control, and nociception.…”

mentioning

confidence: 99%

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Budzik

Garzya

Shi

et al. 2010

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M 1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M 1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M 1 activation.

show abstract

mentioning

confidence: 99%

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Budzik

Garzya

Shi

et al. 2010

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…We recently discovered a novel epigenetic pathway whereby H3K9me3-dependent heterochromatin condensation leads to transcriptional deregulation of muscarinic acetylcholine (Ach) receptor 1 (CHRM1) by occupying its promoter in HD striatal cells [69]. CHRM1 promotes phosphatidylinositol hydrolysis and intracellular Ca 2+ mobilization, while CHRM2 is coupled negatively to adenylate-cyclase activity [72][73][74][75]. The conventional wisdom is that loss of cholinergic receptor function directly results in synaptic dysfunction through inadequate intracellular signal transductions in neurons.…”

Section: Alteration Of Hmt In Hdmentioning

confidence: 99%

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

et al. 2013

View full text Add to dashboard Cite

Huntington's disease (HD) is an incurable and fatal hereditary neurodegenerative disorder of mid-life onset characterized by chorea, emotional distress, and progressive cognitive decline. HD is caused by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Recent studies suggest that epigenetic modifications may play a key role in HD pathogenesis. Alterations of the epigenetic "histone code" lead to chromatin remodeling and deregulation of neuronal gene transcription that are prominently linked to HD pathogenesis. Furthermore, specific noncoding RNAs and microRNAs are associated with neuronal damage in HD. In this review, we discuss how DNA methylation, posttranslational modifications of histone, and noncoding RNA function are affected and involved in HD pathogenesis. In addition, we summarize the therapeutic effects of histone deacetylase inhibitors and DNA binding drugs on epigenetic modifications and neuropathological sequelae in HD. Our understanding of the role of these epigenetic mechanisms may lead to the identification of novel biological markers and new therapeutic targets to treat HD.

show abstract

“…We hoped to measure the difference of binding energy of a phenyl versus cyclohexyl group with each hydrophobic subsite. 23 grade available. All antagonists tested were synthesized in our laboratories.…”

Section: Introductionmentioning

confidence: 99%

Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M₁, cardiac M₂, pancreatic M₃, and striatum M₄ muscarinic receptors

Waelbroeck¹,

Camus²,

Tastenoy³

et al. 1991

Chirality

View full text Add to dashboard Cite

ABSTRACT(R)-Hexahydro-difenidol has a higher affinity for M 1 receptors in NB-OK 1 cells, pancreas M 3 and striatum M 4 receptors (pKi 7.9 to 8.3) than for cardiac M 2 receptors (pKi 7 .0). (8)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance ofthe hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and reeeptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indieated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group <~ dicyclidol) and ofthe cyclohexyl ring by a phenyl moiety <~ difenidol) indueed a !arge (4-to 80-fold) decrease in binding affinity for all musearlnie receptors. Difenidol had a signifieant preference for M 1 , M 3 , and M 4 over M 2 receptors; dicyclidol, by eontrast, had a greater affinity for M 1 and M 4 than for M 2 and M 3 receptors. The binding free energy deerease due to replacement ofthe phenyl and the cyelohexyl groups of(R)-hexahydro-difenidol by, respectively, a eyclohexyl and a phenyl moiety was almostadditive in the ease of M 4 (striatum) binding sites. In the ease ofthe cardiac M 2 , pancreatic M 3 , or NB-OK 1 M 1 receptors the respective binding free energies were not eompletely additive. These results suggest that the four (R)-hexahydro-difenidol ''binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interaetions with the M 1 , M 2 , and M 3 muscarinic receptors. When eaeh of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the musearlnie receptor.

show abstract

Muscarinic Receptor Subtypes

Cited by 161 publications

References 0 publications

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M₁, cardiac M₂, pancreatic M₃, and striatum M₄ muscarinic receptors

Contact Info

Product

Resources

About

Muscarinic Receptor Subtypes

Cited by 161 publications

References 0 publications

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M1, cardiac M2, pancreatic M3, and striatum M4 muscarinic receptors

Contact Info

Product

Resources

About

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists

Stereoselectivity of (R)‐ and (S)‐hexahydro‐difenidol binding to neuroblastoma M₁, cardiac M₂, pancreatic M₃, and striatum M₄ muscarinic receptors