Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 8, Number 10, September 2008

Contents

From Dual Binding Site Acetylcholinesterase Inhibitors to Multi-Target-Directed Ligands (MTDLs): A Step Forward in the Treatment of Alzheimer’s Disease Pp. 960-967
Maria Laura Bolognesi, Anna Minarini, Michela Rosini, Vincenzo Tumiatti and Carlo Melchiorre
[Abstract]


Therapeutic Role of Zonisamide in Neuropsychiatric Disorders Pp.968-975
Muhammad U. Farooq, Philip W. Moore, Archit Bhatt, Rany Aburashed and Mounzer Y. Kassab
[Abstract]


Dopamine D₅ Receptors: A Challenge to Medicinal Chemists Pp. 976-995
G. Giorgioni, A. Piergentili, S. Ruggieri and W. Quaglia
[Abstract]


Fluorescent Agonists and Antagonists for Vasopressin/Oxytocin G Protein-Coupled Receptors: Usefulness in Ligand Screening Assays and Receptor Studies Pp. 996-1005
B. Mouillac, M. Manning and T. Durroux
[Abstract]


From Cochlear Cell Death Pathways to New Pharmacological Therapies Pp. 1006-1019
Jing Wang and Jean-Luc Puel
[Abstract]


Selenium Compounds and Apoptotic Modulation: A New Perspective in Cancer Therapy Pp. 1020-1031
Carmen Sanmartín, Daniel Plano and Juan Antonio Palop
[Abstract]


Flavonoids: Cellular and Molecular Mechanism of Action in Glucose Homeostasis Pp. 1032-1038
Luisa Helena Cazarolli, Leila Zanatta, Elga Heloisa Alberton, Maria Santos Reis Bonorino Figueiredo, Poliane Folador, Rosangela Guollo Damazio, Moacir Geraldo Pizzolatti and Fátima Regina Mena Barreto Silva
[Abstract]


The Use of Technetium-99m Radiolabeled Human Antimicrobial Peptides for Infection Specific Imaging Pp. 1039-1052
C.P.J.M. Brouwer, L. Sarda-Mantel, A. Meulemans, D. Le Guludec and M.M. Welling
[Abstract]


Recent Progress of Src Family Kinase Inhibitors as Anticancer Agents Pp. 1053-1063
Xin Cao, Qi-Dong You, Zhi-Yu Li, Xiao-Jian Wang, Xiao-Yun Lu, Xiao-Rong Liu, Dan Xu and Bao Liu
[Abstract]




Abstracts


[Back to top]
From Dual Binding Site Acetylcholinesterase Inhibitors to Multi-Target-Directed Ligands (MTDLs): A Step Forward in the Treatment of Alzheimer’s Disease
Maria Laura Bolognesi, Anna Minarini, Michela Rosini, Vincenzo Tumiatti and Carlo Melchiorre

Alzheimer’s disease is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-Alzheimer drugs. Recently, however, basis for a therapeutic strategy based on multi-target-directed ligands has been formed. In this context, dual binding site acetylcholinesterase inhibitors represent a suitable starting point. The rational modification of their structures to provide them with additional biological properties has emerged as a successful approach.


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Therapeutic Role of Zonisamide in Neuropsychiatric Disorders
Muhammad U. Farooq, Philip W. Moore, Archit Bhatt, Rany Aburashed and Mounzer Y. Kassab

Zonisamide (ZNS), a sulfonamide antiepileptic drug, is indicated as an adjunct therapy for partial seizure disorders with and without secondary generalization. ZNS has a favorable pharmacokinetic profile because of its rapid absorption and high bioavailability. Its activity is related to the blockade of voltage gated sodium and calcium channels, modulation of central dopaminergic, GABAergic, and serotonergic functions, as well as inhibition of carbonic anhydrase and monoamine oxidase B. ZNS has potential efficacy for an array of neuropsychiatric disorders including migraine and other headache syndromes, neuropathic pain, Parkinson’s disease, essential tremor, stroke, obesity, anxiety, bipolar and binge-eating disorders.


[Back to top]
Dopamine D₅ Receptors: A Challenge to Medicinal Chemists
G. Giorgioni, A. Piergentili, S. Ruggieri and W. Quaglia

Due to the lack of highly selective dopamine D₁ or D₅ receptor ligands, only few data about activation or blocking of these receptor subtypes are available. The present review collects the available information about molecules with notable affinity for D₅ receptor subtype with the purpose to help the researchers to design novel D₅ selective ligands, whose discovery may enrich the knowledge about the physiological function of such a receptor, provide information about its topography, as well as lead to novel potential therapeutic tools.


[Back to top]
Fluorescent Agonists and Antagonists for Vasopressin/Oxytocin G Protein-Coupled Receptors: Usefulness in Ligand Screening Assays and Receptor Studies
B. Mouillac, M. Manning and T. Durroux

Different series of fluorescent agonists and antagonists have been developed and characterized for arginine-vasopressin and oxytocin G protein-coupled receptors. Both cyclic and linear peptide analogs of the neurohypophysial hormones are useful tools for investigating receptor localization and trafficking, analysing receptor structural organization, and developing new receptor-selective high-throughput ligand screening assays.


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From Cochlear Cell Death Pathways to New Pharmacological Therapies
Jing Wang and Jean-Luc Puel

Ototoxic drugs, intense sound or age-related hearing loss recruit most of the apoptotic pathways, but also several additional enzymatic pathways which eventually result in cell death. Here, we discuss therapeutic strategies based on the inhibition of regulators or executors of apoptotic cell death pathways and on the use of antioxidants.


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Selenium Compounds and Apoptotic Modulation: A New Perspective in Cancer Therapy
Carmen Sanmartín, Daniel Plano and Juan Antonio Palop

Recent epidemiological studies have demonstrated that selenium may be an effective chemopreventive and anticancer agent with a broad spectrum against several human cancer cells (prostate, colon, bladder, lung, liver, ovarian, leukemia). A wide range of potential mechanisms have been proposed for the antitumorigenic effects of selenium and these include antiandrogen activity, growth inhibitory effects by regulation of p53 and antioxidant function, and through DNA damage. However, apoptosis is one of the most plausible mechanisms for the anticancer activity. The regulating mechanisms of apoptosis are extremely complex and for selenium compounds they mainly involve a mitochondrial pathway, protein kinases, tumor necrosis factor, activation of caspases and reactive oxygen species. The aim of this review is to summarize the current knowledge about more than twenty eight selenium-containing molecules and to discuss the implications for apoptosis and the impact in cancer therapy.


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Flavonoids: Cellular and Molecular Mechanism of Action in Glucose Homeostasis
Luisa Helena Cazarolli, Leila Zanatta, Elga Heloisa Alberton, Maria Santos Reis Bonorino Figueiredo, Poliane Folador, Rosangela Guollo Damazio, Moacir Geraldo Pizzolatti and Fátima Regina Mena Barreto Silva

The purpose of this review is to discuss the cellular and molecular mechanisms of action of flavonoids focusing on carbohydrate metabolism. The beneficial effects of flavonoids have been studied in relation to diabetes mellitus, either through their capacity to avoid glucose absorption or to improve glucose tolerance. Furthermore, flavonoids stimulate glucose uptake in peripheral tissues, regulate the activity and/or expression of the ratelimiting enzymes in the carbohydrate metabolism pathway and act per se as insulin secretagogues or insulin mimetics, probably, by influencing the pleiotropic mechanisms of insulin signaling, to ameliorate the diabetes status.


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The Use of Technetium-99m Radiolabeled Human Antimicrobial Peptides for Infection Specific Imaging
C.P.J.M. Brouwer, L. Sarda-Mantel, A. Meulemans, D. Le Guludec and M.M. Welling

Bacterial resistance to conventional antibiotics poses a challenge medicine to search for alternatives. Cationic antimicrobial peptides (AMPs) are promising for the development of a new class of antibiotics. This review focuses on the use of technetium-99m labeled synthetic AMPs, derived from human natural cationic AMPs, for target-delivery to and in vivo detection of infection sites caused by (drug-resistant) micro-organisms. The scintigraphic approach has proven to be a reliable method for evaluating AMPs in pharmacological studies and for optimizing target-delivery of radiolabeled AMPs to pathological sites in animals and humans. In addition, the effect of alterations in amphipathicity, amino acid substitution, and dimerization on the biological performance of AMPs is reported. Radiolabeled AMPs offer good perspectives for diagnosis of infections, for monitoring therapy, and, most importantly, for the ability to discriminate between infections and sterile inflammatory processes.


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Recent Progress of Src Family Kinase Inhibitors as Anticancer Agents
Xin Cao, Qi-Dong You, Zhi-Yu Li, Xiao-Jian Wang, Xiao-Yun Lu, Xiao-Rong Liu, Dan Xu and Bao Liu

Src family of protein tyrosine kinases (SFKs) play key roles in regulating signal transduction in cellular processes. However, hyper-activated SFKs lead to uncontrolled cell proliferation and cancers. Many SFKs inhibitors were designed and synthesized as anticancer agents in the past several years and great progress has been made. Herein, some pre-dominant examples of SFKs inhibitors recently developed are reviewed and special attentions are paid to the most important ATP binding site inhibitors.