Phenserine and ring C hetero‐analogues: Drug candidates for the treatment of Alzheimer's disease

Greig, Nigel H.; Pei, Xue‐Feng; Soncrant, Timothy T.; Ingram, Donald K.; Brossi, Arnold

doi:10.1002/med.2610150103

Cited by 190 publications

(187 citation statements)

References 77 publications

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“…Our prior research culminated in the synthesis and characterization of the first available reversible, selective and centrally active BuChE inhibitors to elucidate the role of this enzyme in brain [3,17,18]. Like AChE, BuChE inactivates the neurotransmitter ACh and is a viable new therapeutic target in AD [2][3][4].…”

Section: Discussionmentioning

confidence: 99%

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Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kamal¹,

Klein²,

Luo

et al. 2007

Neurochem Res

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Cholinergic loss is the single most replicated neurotransmitter deficiency in Alzheimer's disease (AD) and has led to the use of acetylcholinesterase inhibitors (AChE-Is) and unselective cholinesterase inhibitors (ChE-Is) as the mainstay of treatment. AChE-Is and ChE-Is, however, induce dose-limiting adverse effects. Recent studies indicate that selective butyrylcholinesterase inhibitors (BuChE-Is) elevate acetylcholine (ACh) in brain, augment long-term potentiation, and improve cognitive performance in rodents without the classic adverse actions of AChE-Is and ChE-Is. BuChE-Is thereby represent a new strategy to ameliorate AD, particularly since AChE activity is depleted in AD brain, in line with ACh levels, whereas BuChE activity is elevated. Our studies have focused on the design and development of cymserine analogues to induce selective time-dependent brain BuChE inhibition, and on the application of innovative and quantitative enzyme kinetic analyses to aid selection of drug candidates. The quantitative interaction of the novel inhibitor, dihydrobenzodioxepine cymserine (DHBDC), with human BuChE was characterized. DHBDC demonstrated potent concentration-dependent binding with BuChE. The IC50 and specific new kinetic constants, such as KT50, PPC, KT1/2 and RI, were determined at dual substrate concentrations of 0.10 and 0.60 mM butyrylthiocholine and reaction times, and are likely attainable in humans. Other classical kinetic parameters such as Kia, Kma, Vma and Vmi were also determined. In synopsis, DHBDC proved to be a highly potent competitive inhibitor of human BuChE in comparison to its structural analogue, cymserine, and represents an interesting drug candidate for AD.

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Section: Discussionmentioning

confidence: 99%

“…1B), to induce time-dependent brain BuChE inhibition [17]. Our design of 'cymserine' analogues [18] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kamal¹,

Klein²,

Luo

et al. 2007

Neurochem Res

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“…This permitted calculation of simple comparative IC50 values of human BuChE by the synthesized compounds. THFBFC, compound 12 with an IC50 of 27 ± 4 nM (Luo et al 2005a), was chosen for further study, herein, due to a combination of its potency for BuChE versus AChE (IC50 2,650 ± 400 nM) and selectivity (<100-fold), together with the knowledge that cymserine analogues are long acting (Greig et al 1995(Greig et al , 2005c. Our more in depth analysis over a concentration range (6-50 nM) that precisely skirts the original IC50 estimate provides a slightly lower value (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To assess this, our studies have focused on the design and development of novel 'drug-like' compounds based on the pharmacophore of the classic short-acting anticholinesterase, (−)-physostigmine, from which we originally derived long-acting (−)-cymserine and its BuChE selective analogues (Greig et al 1995Yu et al 1999) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous efforts culminated in the synthesis of the novel compound, tetrahydrofurobenzofuran cymserine (THFBFC) (Luo et al 2005a(Luo et al , b, 2006, which was loosely based on the backbone of the short-acting anticholinesterase, (−)-physovenine ( Fig. 1), a congener of (−)-physostigmine that similarly is a natural alkaloid deriving from the Calabar bean, Physostigma venenosum (Greig et al 1995). Herein, we characterized the mode and kinetic binding constants of THFBFC through innovative enzyme interaction analyses to assess its suitability as a drug candidate to elucidate the therapeutic potential of BuChE inhibition in AD, as well as to define target concentrations in humans to aid clinical translation.…”

Section: Introductionmentioning

confidence: 99%

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Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

Kamal

et al. 2008

J Neural Transm

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Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to Alzheimer's disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment for several degenerative disorders that culminate in dementia. The primary dose-limiting toxicities of all clinically available AChE-Is are, similar to useful actions on cognition, cholinergically mediated and they ultimately limit the value of this drug class in achieving anything but symptomatic improvements. In addition, AChE levels in brain areas associated with AD decline with disease progression, which likely ultimately limits the therapeutic utility of this drug class. New research indicates that selective inhibition of butyrylcholinesterase (BuChE), a closely related enzyme that is markedly elevated in AD brain, increases acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of AChE-Is. BuChE inhibition hence represents an innovative treatment approach for AD, and agents are currently being synthesized to optimally achieve this. The novel compound, tetrahydrofurobenzofuran cymserine (THFBFC), is derived from our effort to produce a potent and BuChE-selective inhibitor as a candidate to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. Herein, we applied innovative enzyme kinetic analyses to characterize the quantitative interaction of THFBFC with human BuChE. These provided values for the agent's IC50, together with specific new kinetic constants, such as KT50, KT1/2, RI, oKRT, oPmax, KPT and PT1/2, to aid define target concentrations for clinical translation. Additional classical kinetic parameters, including Ki, Km or Ks, kcat or Vmax and Vmi were also determined. THFBFC proved to be a potent competitive inhibitor of human BuChE and, like its isomer dihydrobenzodioxepine cymserine, is a potentially interesting AD drug candidate.

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Unity is Strength

Casali

Saraci

Othman

et al. 2022

More Synthetic Approaches to Nonaromatic Nitrogen Heterocycles

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Phenserine and ring C hetero‐analogues: Drug candidates for the treatment of Alzheimer's disease

Cited by 190 publications

References 77 publications

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

Unity is Strength

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