Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogs

Chen, Yuhpyng L.; Nielsen, Jann A.; Hedberg, Kirk; Dunaiskis, Audrey; Jones, Shawn B.; Russo, Lorena L.; Johnson, Jonathan Jr.; Ives, Jeffrey L.; Liston, Dane

doi:10.1021/jm00086a011

Cited by 46 publications

(17 citation statements)

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“…In particular, it was interesting to examine the low AChE stereoselectivity toward analogs of 8-carbaphysostigmine, since these structures do contain the N(1)- alkyl substituent [39]. Examination of molecular models of the corresponding Michaels complexes indicates that due to bending of the tricyclic moiety at the sp 3 -C 8 , both enantiomers could be accommodated in the hydrophobic pocket without steric occlusion of Trp86.…”

Section: Resultsmentioning

confidence: 99%

Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions

Barak

Ordentlich

Stein

et al. 2008

Biochemical Journal

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The role of the functional architecture of the human acetylcholinesterase (HuAChE) in reactivity toward the carbamates pyridostigmine, rivastigmine and several analogs of physostigmine, that are currently used or considered for use as drugs for Alzheimer’s disease, was analysed using over 20 mutants of residues that constitute the interaction subsites in the active center. Both steps of the HuAChE carbamylation reaction, formation of the Michaelis complex as well as the nucleophilic process, are sensitive to accommodation of the ligand by the enzyme. For certain carbamate - HuAChE combinations, the mode of inhibition shifted from a covalent to a noncovalent type, according to the balance between dissociation and covalent reaction rates. Whereas the charged moieties of pyridostigmine and rivastigmine contribute significantly to the stability of the corresponding HuAChE complexes, no such effect was observed for physostigmine and its analogs, phenserine and cymserine. Moreover, physostigmine-like ligands carrying oxygen instead of nitrogen at position – 1 of the tricyclic moiety (physovenine and tetrahydrofurobenzofuran analogs) displayed comparable structure – function characteristics toward the various HuAChE enzymes. The essential role of the HuAChE hydrophobic pocket, comprising mostly of residues Trp86 and Tyr337, in accommodating (−)-physostigmine and in conferring ~300-fold stereoselectivity toward physostigmines, was elucidated through examination of the reactivity of selected HuAChE mutations toward enantiomeric pairs of different physostigmine analogs. The present study demonstrates that certain charged and uncharged ligands, like analogs of physostigmine and physovenine, seem to be accommodated by the enzyme mostly through hydrophobic interactions.

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Section: Resultsmentioning

confidence: 99%

Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions

Barak

Ordentlich

Stein

et al. 2008

Biochemical Journal

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“…The synthetic route to Phy analogs (pyrrolo [2,3-b]indol-5-ol 3,3a,8,8a-hexahydro-1,3a,8-trimethyl-N-alkyl-carbamates, 3aS-cis) was similar in many respects to the one used for the synthesis of heptylphysostigmine [7]. -1,3a,8-hexahydro-1,2,3,3a,8,8a-pyrrol[2,3-b]indole-5(3aS, 8aR)-heptylphysostignine (6) Five hundered and fifty milligrams of physostigmine (2 mmol) and 108 mg mmol of sodium methoxide (2 mmol) were placed in a flask (50 mL) to which a vacuum between 5 and 10 mm Hg was applied. Absolute ethanol (70 mL) was then added over 2 h in small volumes, under agitation at ambient temperature.…”

Section: Methodsmentioning

confidence: 74%

“…AChE from Electrophorus electricus (Type V-S), acetylthiocholine (ATC), and 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) were purchased from Sigma. Physovenine was provided by Prof. Arnold Brossi and Prof. Nigel H. Greig (NIH, Bethesda) [5] and 8-carbaphysostigmine was provided by Dr. Yuhpyng L.Chen (Pfizer, Groton, CT) [6]. The synthetic route to Phy analogs (pyrrolo [2,3-b]indol-5-ol 3,3a,8,8a-hexahydro-1,3a,8-trimethyl-N-alkyl-carbamates, 3aS-cis) was similar in many respects to the one used for the synthesis of heptylphysostigmine [7].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain

Gavuzzo

Pomponi²

2002

J Biochem & Molecular Tox

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The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second-order rate constant k(on) of the enzyme-inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67-Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the "back door" hypothesis involving facilitated opening for faster product clearance.

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“…Dataset and biological activity The Physostigmine congeners data, represented by anti-acetylcholinesterase activity IC 50 (9.77-20892.96 nM), were obtained from the literature (21)(22)(23). Total 40 Physostigmine derivatives and their corresponding inhibition values are presented in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Ligand‐based 3D‐QSAR Studies of Physostigmine Analogues as Acetylcholinesterase Inhibitors

Ul-Haq¹,

Mahmood

Jehangir

2009

Chem Biol Drug Des

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Natural alkaloid Physostigmine is one of the most potent pseudo-irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long-term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D-QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co-crystallized Ganstigmine as template. The strategy yielded significant 3D-QSAR models with the cross-validated q(2) values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r(2) values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.

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Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogs

Cited by 46 publications

References 0 publications

Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions

Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions

Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain

Ligand‐based 3D‐QSAR Studies of Physostigmine Analogues as Acetylcholinesterase Inhibitors

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