Anticholinergic Drugs

Sastry, B. V. Rama

doi:10.1002/0471266949.bmc095

Cited by 5 publications

(4 citation statements)

References 123 publications

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“…Mp: 164 °C (dec), 250À251 °C. 1 H NMR (300 MHz, CD 3 OD) δ: 2.96 (t, J = 6.0 Hz, 4H), 3.80 (s, 6H), 3.81 (s, 6H), 3.82 (t, J = 6.0 Hz, 4H), 4.69 (s, 4H), 5.47 (s, 4H), 6.84 (s, 2H), 6 1,1 0 -[Biphenyl-3,3 0 -diylbis(methylene)]bis(quinuclidinium) Dibromide (47). White solid.…”

Section: -Cyclohexylpyridine (1g)mentioning

confidence: 99%

“…5 The interest in AChE as a biological target in pharmaceutical research arises from the large number of potential central and peripheral therapeutic activities of AChE inhibitors. More recently developed AChE inhibitors (AChE-Is) address the symptomatic treatment of AD, 6 while older QASs AChE-Is have found a therapeutic application in the treatment of neuromuscular blockade (NMB) in surgical anesthesia, 7 myasthenia gravis (MG), 8 and to a lesser extent in glaucoma. As for the NMB reversal agents, at present, all clinically used drugs, such as neostigmine, pyridostigmine, and edrophonium, are QASs inhibitors of AChE.…”

Section: ' Introductionmentioning

confidence: 99%

“…Mp: 261À263 °C 1. H NMR (400 MHz, CD 3 OD) δ: 2.29 (s, 3H), 5.75 (s, 2H),6.92 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.68 (pst, J = 7.7 Hz, 1H), 7.90 (pst, J 1 = 1.2 Hz, J 2 = 6.9 Hz, J 3 = 8.6 Hz, 1H),7.98 (d, J = 8.8 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 7.3 Hz, 1H). HR LSIMS (m/z) calcd for C 17 H 17 N 2 (M À Br) þ 249.1392; found 249.1398.…”

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confidence: 99%

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Homodimeric Bis-Quaternary Heterocyclic Ammonium Salts as Potent Acetyl- and Butyrylcholinesterase Inhibitors: A Systematic Investigation of the Influence of Linker and Cationic Heads over Affinity and Selectivity

et al. 2011

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A molecular library of quaternary ammonium salts (QASs), mainly composed of symmetrical bis-quaternary heterocyclic bromides exhibiting choline kinase (ChoK) inhibitory activity, were evaluated for their ability to inhibit acetyl- and butyrylcholinesterase (AChE and BChE, respectively). The molecular framework of QASs consisted of two positively charged heteroaromatic (pyridinium or quinolinium) or sterically hindered aliphatic (quinuclidinium) nitrogen rings kept at an appropriate distance by lipophilic rigid or semirigid linkers. Many homodimeric QASs showed AChE and BChE inhibitory potency in the nanomolar range along with a low enzymatic selectivity. Computational studies on AChE, BChE, and ChoK allowed identification of the key molecular determinants for high affinity and selectivity over either one of the three enzymes and guided the design of a hybrid bis-QAS (56) exhibiting the highest AChE affinity (IC(50) = 15 nM) and selectivity over BChE and ChoK (SI = 50 and 562, respectively) and a promising pharmacological potential in myasthenia gravis and neuromuscular blockade.

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Section: -Cyclohexylpyridine (1g)mentioning

confidence: 99%

Section: ' Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Homodimeric Bis-Quaternary Heterocyclic Ammonium Salts as Potent Acetyl- and Butyrylcholinesterase Inhibitors: A Systematic Investigation of the Influence of Linker and Cationic Heads over Affinity and Selectivity

et al. 2011

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“…The distances between the benzene rings and the nitrogen atom in the basic ring in compounds 6 and 7 were estimated to be in the range of 6-8 Å from X-ray crystallographic and modeling studies, similar to the distances reported for atropine and other muscarinic antagonists. [10][11][12] Our previous SAR studies suggested that introduction of the carbamate group at the junction resulted in creation of novel and selective M 3 receptor antagonists, and that both the hydrophobic region and the basic ring influence selectivity for the M 3 receptor. In contrast to 6, which has high affinity and selectivity for the M 3 receptor, quinuclidin-3-yl benzhydrylcarbam- ate (8) showed poor selectivity among the muscarinic receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1,2,3,4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists

et al. 2005

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In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.

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Design, Synthesis, and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium‐like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors

et al. 2010

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A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC(50)=0.236 nM) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N-trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of pi-pi stacking interactions in the AChE peripheral binding site.

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Anticholinergic Drugs

Cited by 5 publications

References 123 publications

Homodimeric Bis-Quaternary Heterocyclic Ammonium Salts as Potent Acetyl- and Butyrylcholinesterase Inhibitors: A Systematic Investigation of the Influence of Linker and Cationic Heads over Affinity and Selectivity

Homodimeric Bis-Quaternary Heterocyclic Ammonium Salts as Potent Acetyl- and Butyrylcholinesterase Inhibitors: A Systematic Investigation of the Influence of Linker and Cationic Heads over Affinity and Selectivity

Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1,2,3,4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists

Design, Synthesis, and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium‐like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors

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