piperidines and Central-Nervous-System-Diseases

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Atrial Fibrillation; Benzamides; Central Nervous System Diseases; Clinical Trials as Topic; Febrile Neutropenia; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Humans; Multicenter Studies as Topic; Myeloid Differentiation Factor 88; Neoplasm Proteins; NF-kappa B; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Receptors, CXCR4; Recurrence; Salvage Therapy; Signal Transduction; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Alkaloids; Animals; Benzodioxoles; Central Nervous System Agents; Central Nervous System Diseases; Dose-Response Relationship, Drug; Drug Interactions; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Molecular hybridization is a recent strategy based on the covalent fusion of two or more pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides (e.g. enkephalins, deltorphins and endomorphins) have been developed, and γ-aminobutyric acid agonists have also been designed for neuropathic pain control. In addition, a number of hybrid compounds have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity, which may be further developed as potential antiepileptic drugs. Moreover, several hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing hybrid compounds including an antioxidant moiety, which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Topics: Analgesics; Central Nervous System Diseases; Choline; Donepezil; Epilepsy; gamma-Aminobutyric Acid; Humans; Indans; Opioid Peptides; Pain; Piperidines; Tacrine

Topics: Animals; Brain; Camphanes; Carbazoles; Carrier Proteins; Central Nervous System Diseases; Drug Discovery; GABA Plasma Membrane Transport Proteins; GABA Uptake Inhibitors; Humans; Isoxazoles; Mental Disorders; Molecular Targeted Therapy; Nipecotic Acids; Piperidines; Tiagabine

The endogenous cannabinoid system is a novel, remarkably elaborate physiological signaling system, comprising the recently identified endogenous cannabinoid ligands, their corresponding selective receptors, and the machinery of proteins and enzymes that is involved in their biosynthesis, release, transport, and degradation. This system extends widely in both the central nervous system (CNS) and the periphery and exhibits a variety of actions implicated in vital functions (e.g., behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic). Particular interest has been focused on the apparent participation of endocannabinoids in metabolic homeostasis by modulating the activity of CNS circuits that control food intake and energy expenditure, the neuroendocrine response of the stress system, and the metabolic functions of crucial peripheral tissues, such as the adipose tissue, the gastrointestinal tract, the liver, and the skeletal muscles. These effects are predominantly CB(1) receptor mediated and, thus, selective antagonists of this receptor subtype are being vigorously investigated as potential therapeutic agents for the treatment of various metabolic derangements (e.g., obesity, insulin resistance, dyslipidemia, and metabolic syndrome). The first selective CB(1) receptor antagonist, rimonabant, has already successfully completed phase III clinical trials as adjunctive obesity treatment, with significant improvements in several associated metabolic and cardiovascular risk factors that led to the recent approval of its clinical use by the Food and Drug Administration.

Topics: Cannabinoid Receptor Modulators; Central Nervous System Diseases; Clinical Trials as Topic; Endocannabinoids; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Signal Transduction

The NMDAR2B subunit is the focus of increasing interest as a therapeutic target in a wide range of CNS pathologies, including acute and chronic pain, stroke and head trauma, drug-induced dyskinesias, and dementias. Due to significant pharmaceutical endeavor, an impressive collection of chemical leads has been developed which target the NR2B subunit, some of which appear to discriminate between closely related subtypes. We now have the benefit of a structural template for the ifenprodil binding site which should further improve future structure activity relationships. A growing appreciation of the likely extrasynaptic localisation of the NR2B receptor subtype and importance of NR2B protein modification, notably tyrosine phosphorylation, may explain its therapeutic importance. The apparent superior preclinical and clinical data for the second and third generation NR2B compounds is likely to reflect subtype selectivity, a unique mode of action and cellular location of the NR2B receptors in the CNS.

Topics: Animals; Binding Sites; Central Nervous System Diseases; Cognition; Drug Delivery Systems; Humans; Neuroprotective Agents; Phenols; Phosphorylation; Piperidines; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.

Topics: Aged; Alzheimer Disease; Animals; Basal Ganglia Diseases; Bradycardia; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Double-Blind Method; Drug Evaluation; Drug Interactions; Female; Galantamine; Gastrointestinal Diseases; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Memantine; Meta-Analysis as Topic; Mice; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Single-Blind Method; Sleep Wake Disorders; Treatment Outcome

The GABA(A) receptor system is implicated in a number of neurological diseases, making GABA(A) receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the GABA(A) receptor complex, reflecting the very strict structural requirements for GABA(A) receptor recognition and activation. Within the series of compounds showing agonist activity at the GABA(A) receptor site that have been developed, most of the ligands are structurally derived from the GABA(A) agonists muscimol, THIP or isoguvacine. Using recombinant GABA(A) receptors, functional selectivity has been shown for a number of compounds such as the GABA(A)agonists imidazole-4-acetic acid and THIP, showing highly subunit-dependent potency and maximal response. In the light of the interest in partial GABA(A) receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA(A) agonist, have been performed. In this connection, a series of GABA(A) ligands has been developed showing pharmacological profiles from moderately potent low-efficacy partial GABA(A) agonist activity to potent and selective antagonist effect. Only little information about direct acting GABA(A) receptor agonists in clinical studies is available. Results from clinical studies on the effect of the GABA(A) agonist THIP on human sleep pattern shows that the functional consequences of a direct acting agonist are different from those seen after administration of GABA(A) receptor modulators.

Topics: Animals; Central Nervous System Diseases; GABA Agents; GABA Agonists; GABA Antagonists; Humans; Isonicotinic Acids; Isoxazoles; Ligands; Muscimol; Piperidines; Protein Subunits; Receptors, GABA-A

Topics: Administration, Oral; Adult; Aged; Alanine Transaminase; Angina Pectoris; Blood Pressure; Body Weight; Central Nervous System Diseases; Clinical Trials as Topic; Drug Evaluation; Electrocardiography; Female; Gastrointestinal Diseases; Heart Rate; Humans; Male; Middle Aged; Perhexiline; Physical Exertion; Piperidines; Placebos; Tachycardia; Vasodilator Agents

Topics: Adenine; Cell Transformation, Neoplastic; Central Nervous System Diseases; Female; Humans; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Central Nervous System Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Central Nervous System Diseases; Female; Humans; Immunoglobulin M; Leukocyte Count; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist.. Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments.. (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084.. (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.

Topics: Biphenyl Compounds; Central Nervous System Diseases; Dose-Response Relationship, Drug; Humans; Molecular Structure; Morpholines; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

Previously we designed a series of pyridinic anticholinesterasic compounds based on molecular hybridization between tacrine and the natural piperidine alkaloid (-)-3-O-acetylspectaline isolated from Senna spectabilis. Based on the information that the cholinergic system has an important role in the treatment of schizophrenia and depression, we herein report the evaluation of a series of pyridinic compounds in animal models for antipsychotic and antidepressant-like activities. Compound 2 decreased the immobility time of mice in the forced swimming test (5 and 10mg/kg p.o.) and prevented the climbing behavior induced by apomorphine (10mg/kg, p.o.), without impairing animals locomotor activity.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Central Nervous System Diseases; Disease Models, Animal; Mice; Piperidines; Pyridines; Schizophrenia

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Acetamides; Anti-Ulcer Agents; Central Nervous System Diseases; Clopidogrel; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Pyridines; Rabeprazole; Stomach Ulcer; Ticlopidine

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Cannabinoids; Central Nervous System; Central Nervous System Diseases; Drug Approval; Germany; Humans; Mental Disorders; Metabolic Syndrome; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

It has been suggested that triptans achieving higher central nervous system (CNS) levels should have an advantage in efficacy, if central actions are important. Objective.-Our aim was to correlate the efficacy and tolerability results of triptans with their lipophilicity.. Data for response and pain free at 2 hours, recurrence, adverse events (AE), CNS AE, and chest symptoms taken from Ferrari et al's meta-analysis publications for the recommended doses of oral triptans were correlated with their lipophilicity coefficients (logD(pH)7.4 = -2.1 almotriptan < -1.5 sumatriptan < -1.0 zolmitriptan < -0.7 rizatriptan < -0.2 naratriptan < 0.5 eletriptan).. We found no significant correlation between lipophilicity coefficients and any of the analyzed parameters. There was, however, some correlation between lipophilicity and CNS AE (P = .09, r = 0.74) and, to a lesser degree, with a reduction in recurrence rate (r = -0.36). The r values for response and pain free with placebo correction ranged from 0.04 to 0.34, suggesting almost no correlation between lipophilicity and efficacy variables.. According to this analysis, a higher lipophilicity does not seem crucial to improve triptan efficacy. This physico-chemical property, however, correlates with higher CNS AE and, possibly, lower recurrence rates.

Topics: Central Nervous System Diseases; Chemical Phenomena; Chemistry, Physical; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Statistics as Topic; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.

Topics: Animals; Carboxylic Acids; Central Nervous System Diseases; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity; In Vitro Techniques; Male; Mice; Mice, Inbred Strains; Piperazines; Piperidines; Rats; Rats, Wistar

In addition to the motor events associated with high pressure neurologic syndrome (HPNS), we have observed behavioral changes that resemble the 5-hydroxytryptamine (5-HT) syndrome in free-moving rats exposed to pressures up to 70 ATA. These include a flat body posture, head weaving, reciprocal forepaw treading, and hyperlocomotion. Such changes occur when brain 5-HT levels are raised or when 5-HT receptors are activated. We have therefore studied the behavior of rats at pressure treated either with saline or with one of the following drugs: p-chlorophenylalanine (pCPA) which depletes brain 5-HT by 85-90%, Wy 27587 which inhibits 5-HT reuptake, 5-hydroxytryptophan (5-HTP) and carbidopa which increase brain 5-HT synthesis, and quipazine which is a 5-HT receptor-agonist. After treatment, rats were individually exposed to pressure, and behavioral scores were made for 5 min every 10 ATA up to 70 ATA by an unbiased observer who was not aware of the treatment given. Analysis of all control rats indicated that only a flat body posture, forepaw treading, and hyperlocomotion were positively correlated with pressure, and these events were used in all subsequent analysis. Rats treated with pCPA with whole brain 5-HT levels reduced by 90% had scores significantly less than controls. Rats treated with Wy 27587 showed significantly increased scores. Rats treated with 5-HTP and quipazine failed to show a significant increase in scores. These results suggest that a modified form of the 5-HT syndrome occurs when rats are exposed to increased pressure, and the behavioral events seen are consistent with some activation of the 5-HT1A receptor subtype.

Topics: 5-Hydroxytryptophan; Animals; Atmospheric Pressure; Behavior, Animal; Brain; Carbidopa; Central Nervous System Diseases; Fenclonine; High Pressure Neurological Syndrome; Hydroxyindoleacetic Acid; Male; Niacinamide; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists

Topics: Adolescent; Adult; Aged; Amygdala; Astrocytoma; Brain Neoplasms; Central Nervous System Diseases; Cerebral Cortex; Chronic Disease; Electroencephalography; Electrophysiology; Epilepsy, Temporal Lobe; Female; Humans; Male; Mental Disorders; Middle Aged; Parasympatholytics; Piperidines; Temporal Lobe