Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR

Texier, Laurence Le; Favre, Edith; Ronzani, N.; Blavet, N.; Pirotzky, E.; Godfroid, Jean‐Jacques

doi:10.1016/0929-7855(95)00053-4

Cited by 14 publications

(18 citation statements)

References 39 publications

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“…Indeed, integrated pharmacology may already exist for many drugs and is conceptually a basis for cutting-edge drug discovery. Anti-PAF and anti-acetylcholinesterase activities have been combined in a single drug molecule as potential therapy for senile dementia of the Alzheimer type (Texier et al, 1996). Furthermore, only molecules with both activities protect against scopolamine-induced amnesia (Texier et al, 1996).…”

Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 99%

“…Anti-PAF and anti-acetylcholinesterase activities have been combined in a single drug molecule as potential therapy for senile dementia of the Alzheimer type (Texier et al, 1996). Furthermore, only molecules with both activities protect against scopolamine-induced amnesia (Texier et al, 1996). Platelet-activating factor is a dual pro-inflammatory and neuromessenger phospholipid molecule that serves many physiological functions and illustrates the multifavious nature of neuroimmunology (Bazan, 1998).…”

Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 99%

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Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.

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Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 99%

Section: Multiple Drug/agent Actions and Mtmcsmentioning

confidence: 99%

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Cowan¹,

Broomfield²,

Lenz³

et al. 2003

J of Applied Toxicology

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“…The synthesis of PMS777 was previously described (Le Texier et al 1996). PAF (1-Oalkyl-2-acetyl-sn-glycero-3-phosphocholine) and BN52021 (ginkgolide B), a positive control of PAF receptor antagonist, were purchased from Sigma.…”

Section: Drugsmentioning

confidence: 99%

PMS777, A Bis-interacting Ligand for PAF Receptor Antagonism and AChE Inhibition, Attenuates PAF-induced Neurocytotoxicity in SH-SY5Y Cells

Shao

Zhu

et al. 2007

Cell Mol Neurobiol

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(1) HIV-1 and viral proteins-evoked chronic brain inflammation, which is characterized by microglial activation, is the pivotal neuropathogenesis of HIV-1-associated dementia (HAD). Platelet-activating factor (PAF), mainly released from activated microglia and acts as a high potent inflammatory mediator and a neurotoxin, is indicated to be a principle initiator of neuroinflammation, neuronal dysfunction, and apoptosis related to HAD. Thus, bis-interacting ligands of acetylcholinesterase (AChE) inhibition and PAF receptor antagonism would be of great interest in the therapeutic potential of HAD not only for improvement of cognitive performance, but also for disease-modifying. (2). We have previously reported that a novel tetrahydrofuran-derived bis-interacting ligand PMS777 had satisfying potencies for PAF receptor blockade and AChE inhibition, and markedly improved cholinergic dysfunction-induced cognitive impairment in mice. Continuing with our research, we further investigated the neuroprotective activities of PMS777 on PAF-triggered neuronal injury in human neuroblastoma SH-SY5Y cells. (3) The bis-interacting ligand PMS777 (10 muM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca(2+) overload, down-regulation of anti-apoptotic bcl-2 mRNA, stimulation of pro-apoptotic bax mRNA expression and activation of caspase-3 pathway. Also, PMS777 could fine-tune pro-inflammatory cyclooxygenase-2 (cox-2) mRNA expression in PAF-treated cells. (4) These results suggest that PMS777 possesses a neuroprotective profile via anti-apoptotic/inflammatory signaling and warrant further investigations in connection with the potential value of this compound in HAD treatment.

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“…PMS777 (Fig. 1) is one of a family of new cholinesterase inhibitors synthesized by Le Texier et al that also has anti-platelet activated factor (PAF) activity [11,12]. Previous studies have indicated that PMS777 inhibited acetylcholinesterase activity with IC50 at 0.8 lM and antagonized PAF activity with IC50 at 8 lM [11,12].…”

Section: Introductionmentioning

confidence: 99%

PMS777, a New Cholinesterase Inhibitor with Anti-Platelet Activated Factor Activity, Regulates Amyloid Precursor Protein Processing In Vitro

et al. 2008

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and cognition. Previous data have shown that beta-amyloid (Abeta) cascade plays a central role in AD pathophysiology and thus drugs regulate amyloid precursor protein (APP) metabolism may have therapeutic potential. Here the effects of PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, on APP processing were investigated. Using SH-SY5Y(APP695) cells, it showed that PMS777 treatment caused significant decreased secretion of sAPPalpha into the conditioned media without affecting cellular holoAPP synthesis. When PC12 cells were incubated with PMS777, the same effect was observed. The data also indicated that 10 muM PMS777 incubation decreased the release of Abeta42 into the cell media as compared with vehicle group in SH-SY5Y(APP695) cells. Pretreatment of cells with M-receptor scopolamine antagonized the decreased secretion of sAPPalpha induced by PMS777, but N-receptor alpha-bungarotoxin pretreatment did not have such an effect. These results indicated that PMS777 could modulate APP processing in vitro and that decreasing Abeta generation might demonstrate its therapeutic potential in AD.

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Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR

Cited by 14 publications

References 39 publications

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

Putative role of proteolysis and inﬂammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi‐threat medical countermeasures

PMS777, A Bis-interacting Ligand for PAF Receptor Antagonism and AChE Inhibition, Attenuates PAF-induced Neurocytotoxicity in SH-SY5Y Cells

PMS777, a New Cholinesterase Inhibitor with Anti-Platelet Activated Factor Activity, Regulates Amyloid Precursor Protein Processing In Vitro

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