benzofurans and Central-Nervous-System-Diseases

Antimuscarinic drug therapy has been shown to be effective in the management of patients with symptoms of the overactive bladder syndrome (OAB), but the bothersome antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision often affect compliance with medication. The development of bladder selective M3 specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. The M3 specific antagonist solifenacin has recently been marketed, and darifenacin will soon be available. The purpose of this article is to review the pharmacology and clinical trial data available for darifenacin, in addition to examining its role in the treatment of the OBS.

Topics: Absorption; Benzofurans; Central Nervous System Diseases; Drug Interactions; Drug Tolerance; Heart Rate; Humans; Muscarinic Antagonists; Pyrrolidines; Receptors, Muscarinic; Treatment Outcome; Urinary Bladder Diseases; Urination Disorders

Epilepsy and CNS injury identify a heterogenous group of diseases, many of which exhibit refractoriness (e.g., the partial epilepsies) to established drug therapy or, as in the case of brain and spinal cord injuries of variable etiologies, remain a formidable target for successful drug development. As such, the search for safe, effective antiepileptic and neuroprotective drugs continues. Although several CNS targets have been identified for drug development, especially the excitatory amino acid receptors, free-radical systems, gangliosides, and nitric oxide, etc., the opioid system and its diversity of receptors have, until recently, received little attention. This review attempts to focus on one opioid system, namely the kappa receptor class of opioid ligands, specifically addressing the potential anticonvulsant and neuroprotective properties of the arylacetamide series of kappa opioid analgesics as novel pharmacotherapeutic approaches to the treatment of epilepsy, stroke, or trauma related brain or spinal cord injury.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Benzofurans; Central Nervous System Diseases; Epilepsy; Humans; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Thiophenes

The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Blood-Brain Barrier; Central Nervous System Diseases; Humans; Inflammation; Metabolic Diseases; Neuroprotection; Oxidative Stress; Resveratrol; Stilbenes; tau Proteins

Natural products from lichens are widely investigated for their biological properties, yet their potential as central nervous system (CNS) therapeutic agents is less explored.. The present study investigated the neuroactive properties of selected lichen compounds (atranorin, perlatolic acid, physodic acid and usnic acid), for their neurotrophic, neurogenic and acetylcholine esterase (AChE) activities.. Neurotrophic activity (neurite outgrowth) was determined using murine neuroblastoma Neuro2A cells. A MTT assay was performed to assess the cytotoxicity of compounds at optimum neurotrophic activity. Neuro2A cells treated with neurotrophic lichen compounds were used for RT-PCR to evaluate the induction of genes that code for the neurotrophic markers BDNF and NGF. Immunoblotting was used to assess acetyl H3 and H4 levels, the epigenetic markers associated with neurotrophic and/or neurogenic activity. The neurogenic property of the compounds was determined using murine hippocampal primary cultures. AChE inhibition activity was performed using a modified Ellman's esterase method.. Lichen compounds atranorin, perlatolic acid, physodic acid and (+)-usnic acid showed neurotrophic activity in a preliminary cell-based screening based on Neuro2A neurite outgrowth. Except for usnic acid, no cytotoxic effects were observed for the two depsides (atranorin and perlatolic acid) and the alkyl depsidone (physodic acid). Perlatolic acid appears to be promising, as it also exhibited AChE inhibition activity and potent proneurogenic activity. The neurotrophic lichen compounds (atranorin, perlatolic acid, physodic acid) modulated the gene expression of BDNF and NGF. In addition, perlatolic acid showed increased protein levels of acetyl H3 and H4 in Neuro2A cells.. These lichen depsides and depsidones showed neuroactive properties in vitro (Neuro2A cells) and ex vivo (primary neural stem or progenitor cells), suggesting their potential to treat CNS disorders.

Topics: Acetylcholinesterase; Animals; Benzoates; Benzofurans; Biological Products; Brain-Derived Neurotrophic Factor; Cell Line; Central Nervous System; Central Nervous System Diseases; Cholinesterase Inhibitors; Depsides; Dibenzoxepins; Gene Expression; Hydroxybenzoates; Lactones; Lichens; Mice; Nerve Growth Factor; Neural Stem Cells; Neurogenesis

The α2-adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2-AR subtypes (α2A , α2B and α2C ) have been available, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1-AR agonist-evoked responses in vivo were used to demonstrate the α2C-AR selectivity for ORM-10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801. The Kb values of in vitro α2C-AR antagonism for ORM-10921 varied between 0.078-1.2 nM depending on the applied method. The selectivity ratios compared to α2A-AR subtype and other relevant receptors were 10-100 times in vitro. The in vivo experiments supported its potent α2C-antagonism combined with only a weak α2A-antagonism. In the pharmacodynamic microdialysis study, ORM-10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions. In the behavioural tests, ORM-10921 displayed potent antidepressant and antipsychotic-like effects in the forced swimming test and prepulse-inhibition models analogously with the previously reported results with structurally different α2C-selective AR antagonist JP-1302. Our new results also indicate that ORM-10921 alleviated the NMDA-antagonist-induced impairments in social behaviour and watermaze navigation. This study extends and further validates the concept that α2C -AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C-antagonism to treat such disorders.

Topics: Acridines; Adrenergic alpha-2 Receptor Antagonists; Animals; Antidepressive Agents; Benzofurans; Central Nervous System; Central Nervous System Diseases; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Hypothermia; Male; Mice; Neuroprotective Agents; Phencyclidine; Piperazines; Quinolizidines; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2

Topics: Amiodarone; Benzofurans; Central Nervous System Diseases; Drug Administration Schedule; Eye Diseases; Gastrointestinal Diseases; Heart Conduction System; Humans; Liver; Peripheral Nervous System Diseases; Pulmonary Fibrosis; Skin Diseases; Thyroid Diseases