Binding profile of benextramine at neuropeptide Y receptor subtypes in rat brain areas

Melchiorre, Carlo; Romualdi, Patrizia; Bolognesi, María Laura; Donatini, A.; Ferri, Sergio Solbes

doi:10.1016/0014-2999(94)90228-3

Cited by 13 publications

(15 citation statements)

References 12 publications

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“…Another example of early developments of dual binding site AChEIs is caproctamine ( 16 , Fig. ) a polyamine‐based dual inhibitor of AChE designed from benextramine, a muscarinic receptor (M) M 2 antagonist. Caproctamine was able to inhibit AChE (IC 50 = 0.17 µM) and block the M2 muscarinic receptor (M 2 K b = 0.66 µM) .…”

Section: Dual Binding Site Ache Inhibitorsmentioning

confidence: 99%

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

León

Garcı́a

Marco‐Contelles

2011

Medicinal Research Reviews

409

256

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With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one‐compound‐one‐target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium‐permeable channels such as voltage‐dependent calcium channels, N‐methyl‐D‐aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one‐compound‐various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. © 2011 Wiley Periodicals, Inc. Med Res Rev

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Section: Dual Binding Site Ache Inhibitorsmentioning

confidence: 99%

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

León

Garcı́a

Marco‐Contelles

2011

Medicinal Research Reviews

409

256

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“…Without an antagonist of NPY receptors, it has been difficult to produce definitive evidence for such a role of NPY. Recently Laher et al (1994) (Doughty et al, 1990;Tessel et al, 1993;Melchiorre et al, 1994). However, the affinity of benextramine for many other receptors (Lew & Angus, 1984) and particularly for L-type calcium channels (Plotek & Atlas, 1983) Pharmacology (1996) 117,[1768][1769][1770][1771][1772] ([2',4],[2,4'] homodimer of Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-ArgTyr-CONH2 where Dpr is diaminopropionic acid) designated peptide IA (Daniels et al, 1994) or 1229U91 (Daniels et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of a selective peptide antagonist of neuropeptide Y vascular postsynaptic receptors

Lew

Murphy

Angus

1996

British J Pharmacology

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“…Benextramine has been known to irreversibly bind to ␣ 2 -adrenoceptors (Melchiorre, 1981;Belleau et al, 1982b;Lew and Angus, 1984;Hieble et al, 1985;Timmermans et al, 1985;Taouis et al, 1987;McKernan et al, 1988;Brink et al, 2000;Umland et al, 2001), 5-HT 1A -serotonergic receptors (Stanton and Beer, 1997), H 2 -histaminergic receptors (Belleau et al, 1982a), and neuropeptide Y receptors (Melchiorre et al, 1994). Present knowledge regarding the mechanism of action of benextramine is limited to the observations from predominantly radioligand binding studies, and it is generally assumed that benextramine irreversibly inactivates the ligand (primary or syntopic) binding sites at these receptors.…”

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confidence: 99%

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

J Pharmacol Exp Ther

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Many irreversible antagonists have been shown to inactivate G protein-coupled receptors (GPCRs) and used to study agonists and spare receptors. Presumably, they bind to primary (agonist) binding sites on the GPCR, although noncompetitive mechanisms of antagonism have been demonstrated but not thoroughly investigated. We studied noncompetitive antagonism by phenoxybenzamine and benextramine at ␣ 2A -adrenoceptors in stably transfected Chinese hamster ovary cells, benextramine and 4-diphenylacetoxy-N-[2-chloroethyl]piperidine hydrochloride (4-DAMP mustard) at endogenous muscarinic acetylcholine (mACh) receptors in human neuroblastoma SH-SY5Y cells, and benextramine at serotonin 5-HT 2A

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Binding profile of benextramine at neuropeptide Y receptor subtypes in rat brain areas

Cited by 13 publications

References 12 publications

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

Synthesis and characterization of a selective peptide antagonist of neuropeptide Y vascular postsynaptic receptors

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

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