piperidines has been researched along with 4-aminopiperidine* in 36 studies
1 trial(s) available for piperidines and 4-aminopiperidine
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Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study.
Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS.. To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not.. Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed.. Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus).. Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms. Topics: Abdominal Pain; Adolescent; Adult; Aged; Anxiety; Arousal; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Emotions; Female; Humans; Irritable Bowel Syndrome; Middle Aged; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Pilot Projects; Piperidines; Receptors, Neurokinin-1; Stress, Psychological; Visceral Pain; Young Adult | 2012 |
35 other study(ies) available for piperidines and 4-aminopiperidine
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Synthesis, Biological Evaluation, and Structure-Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis.
The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from Topics: Antifungal Agents; Aspergillus; Biosynthetic Pathways; Candida; Drug Discovery; Ergosterol; Fungi; Humans; Mucorales; Mycoses; Piperidines; Structure-Activity Relationship | 2021 |
Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly.
The majority of FDA-approved HCV therapeutics target the viral replicative machinery. An automated high-throughput phenotypic screen identified several small molecules as potent inhibitors of hepatitis C virus replication. Here, we disclose the discovery and optimization of a 4-aminopiperidine (4AP) scaffold targeting the assembly stages of the HCV life cycle. The original screening hit (1) demonstrates efficacy in the HCVcc assay but does not show potency prior to or during viral replication. Colocalization and infectivity studies indicate that the 4AP chemotype inhibits the assembly and release of infectious HCV. Compound 1 acts synergistically with FDA-approved direct-acting antiviral compounds Telaprevir and Daclatasvir, as well as broad spectrum antivirals Ribavirin and cyclosporin A. Following an SAR campaign, several derivatives of the 4AP series have been identified with increased potency against HCV, reduced Topics: Animals; Antiviral Agents; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Hepacivirus; Humans; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Rats; Structure-Activity Relationship; Virus Replication | 2021 |
Identification of entry inhibitors with 4-aminopiperidine scaffold targeting group 1 influenza A virus.
Topics: A549 Cells; Antiviral Agents; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Piperidines; Small Molecule Libraries; Structure-Activity Relationship; Virus Internalization; Virus Replication | 2020 |
Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.
A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1. Topics: Amides; Calcitonin Gene-Related Peptide Receptor Antagonists; Chemistry Techniques, Synthetic; Lactams; Phenol; Piperidines; Receptors, Calcitonin Gene-Related Peptide | 2019 |
POm Thalamocortical Input Drives Layer-Specific Microcircuits in Somatosensory Cortex.
Higher-order thalamic nuclei, such as the posterior medial nucleus (POm) in the somatosensory system or the pulvinar in the visual system, densely innervate the cortex and can influence perception and plasticity. To systematically evaluate how higher-order thalamic nuclei can drive cortical circuits, we investigated cell-type selective responses to POm stimulation in mouse primary somatosensory (barrel) cortex, using genetically targeted whole-cell recordings in acute brain slices. We find that ChR2-evoked thalamic input selectively targets specific cell types in the neocortex, revealing layer-specific modules for the summation and processing of POm input. Evoked activity in pyramidal neurons from deep layers is fast and synchronized by rapid feedforward inhibition from GABAergic parvalbumin-expressing neurons, and activity in superficial layers is weaker and prolonged, facilitated by slow inhibition from GABAergic neurons expressing the 5HT3a receptor. Somatostatin-expressing GABAergic neurons do not receive direct input in either layer and their spontaneous activity is suppressed during POm stimulation. This novel pattern of weak, delayed, thalamus-evoked inhibition in layer 2 suggests a longer integration window for incoming sensory information and may facilitate stimulus detection and plasticity in superficial pyramidal neurons. Topics: Animals; Channelrhodopsins; Excitatory Amino Acid Antagonists; Inhibitory Postsynaptic Potentials; Mice; Mice, Inbred C57BL; Nerve Net; Neural Pathways; Parvalbumins; Piperidines; Potassium Channel Blockers; Pyramidal Cells; Quinoxalines; Receptors, Serotonin, 5-HT3; Sodium Channel Blockers; Somatosensory Cortex; Somatostatin; Tetrodotoxin; Thalamic Nuclei; Vasoactive Intestinal Peptide | 2018 |
The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons.
Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5-200 μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation. Topics: Action Potentials; Analgesics, Non-Narcotic; Animals; Autistic Disorder; Biotin; Cardiovascular Agents; Dopaminergic Neurons; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Piperidines; Pluripotent Stem Cells; Potassium Channel Blockers; Pyrimidines; Quinine; Sodium Channel Blockers; Substantia Nigra; Tetrodotoxin; Tyrosine 3-Monooxygenase | 2018 |
Toxicological evaluation of convulsant and anticonvulsant drugs in human induced pluripotent stem cell-derived cortical neuronal networks using an MEA system.
Functional evaluation assays using human induced pluripotent stem cell (hiPSC)-derived neurons can predict the convulsion toxicity of new drugs and the neurological effects of antiepileptic drugs. However, differences in responsiveness depending on convulsant type and antiepileptic drugs, and an evaluation index capable of comparing in vitro responses with in vivo responses are not well known. We observed the difference in synchronized burst patterns in the epileptiform activities induced by pentylentetrazole (PTZ) and 4-aminopryridine (4-AP) with different action mechanisms using multi-electrode arrays (MEAs); we also observed that 100 µM of the antiepileptic drug phenytoin suppressed epileptiform activities induced by PTZ, but increased those induced by 4-AP. To compare in vitro results with in vivo convulsive responses, frequency analysis of below 250 Hz, excluding the spike component, was performed. The in vivo convulsive firing enhancement of the high γ wave and β wave component were observed remarkably in in vitro hiPSC-derived neurons with astrocytes in co-culture. MEA measurement of hiPSC-derived neurons in co-culture with astrocytes and our analysis methods, including frequency analysis, appear effective for predicting convulsion toxicity, side effects, and their mechanism of action as well as the comparison of convulsions induced in vivo. Topics: Action Potentials; Anticonvulsants; Astrocytes; Cell Differentiation; Cells, Cultured; Cerebellar Cortex; Coculture Techniques; Convulsants; Ethanolamines; Humans; Induced Pluripotent Stem Cells; Landau-Kleffner Syndrome; Neuronal Plasticity; Neurons; Piperidines | 2018 |
Anticonvulsant profile of the neuroactive steroid, SGE-516, in animal models.
Despite the availability of multiple antiepileptic drugs (AED), failure to adequately control seizures is a challenge for approximately one third of epilepsy patients, and new therapies with a differentiated mechanism of action are needed. The neuroactive steroid, SGE-516, is a positive allosteric modulator of both gamma- and delta-containing GABA Topics: Action Potentials; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Electroshock; Fragile X Mental Retardation Protein; gamma-Aminobutyric Acid; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Knockout; Pentylenetetrazole; Piperidines; Potassium Channel Blockers; Pregnanolone; Rats; Rats, Sprague-Dawley; Seizures | 2017 |
Evaluation and Modeling of Vapor-Liquid Equilibrium and CO
Novel absorbents with improved characteristics are required to reduce the existing cost and environmental barriers to deployment of large scale CO Topics: Carbon Dioxide; Diamines; Piperidines; Thermodynamics; Water | 2017 |
Helical Oligopeptides of a Quaternized Amino Acid with Tunable Chiral-Induction Ability and an Anomalous pH Response.
A series of octamer (8-mer) and hexadecamer (16-mer) oligopeptides of 4-aminopiperidine-4-carboxylic acid (Api) with l-leucine as a chiral auxiliary at their N or C termini were synthesized. By using circular dichroism spectroscopy, the conformational profiles of the peptides were systematically studied, which revealed that the α-helix-formation ability of the peptides is determined by the combination of parameters, which includes peptide length, state of the piperidine groups in the Api units, and position of the chiral auxiliary. When the piperidines were in the free-base state, the peptides showed a low propensity to form helical structures. However, the protonation and acylation of the piperidines enhanced the formation of helical structures, such that the order for helix-formation ability was protonated>acylated>free base. In terms of peptide length, the 16-mers generally showed higher helix-formation ability than the corresponding 8-mers, and one of the 16-mers showed helicity at the highest level reported thus far for oligopeptides of a similar length. It was also found that the sensitivity of the helical structure towards the state of the piperidine groups changed drastically depending on the chiral auxiliary position; the N-terminal chiral peptides were more sensitive than the C-terminal chiral analogues. Topics: Amino Acids; Circular Dichroism; Hydrogen-Ion Concentration; Oligopeptides; Piperidines; Protein Structure, Secondary; Stereoisomerism | 2017 |
Pyrazole antagonists of the CB1 receptor with reduced brain penetration.
Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant. Topics: Animals; Brain; Humans; Male; Piperidines; Pyrazoles; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant | 2016 |
The 4-aminopiperidine series has limited anti-tubercular and anti-staphylococcus aureus activity.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is the leading cause of death from a bacterial infection. The 4-aminopiperidine (PIP) series has been reported as having anti-bacterial activity against M. tuberculosis. We explored this series for its potential to inhibit aerobic growth of M. tuberculosis. We examined substitution at the N-1 position and C-4 position of the piperidine and modifications of the piperidine moiety systematically to delineate structure-activity relationships influencing potency. Compounds were tested for growth-inhibitory activity against virulent M. tuberculosis. A selected set of compounds were also tested for its activity against Staphylococcus aureus.. The compound with a norbornenylmethyl substituent at the N-1 position and N-benzyl-N-phenethylamine at the C-4 position of the piperidine (1) was the only active compound with a minimum inhibitory concentration (MIC) of 10 μM against M. tuberculosis. Compounds were not active against S. aureus.. We were unable to derive any other analogs with MIC < 20 μM against M. tuberculosis. Therefore we conclude that the lack of activity is a liability in this series precluding it from further development. Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Staphylococcus aureus; Structure-Activity Relationship; Vero Cells | 2015 |
Can Neural Activity Propagate by Endogenous Electrical Field?
It is widely accepted that synaptic transmissions and gap junctions are the major governing mechanisms for signal traveling in the neural system. Yet, a group of neural waves, either physiological or pathological, share the same speed of ∼0.1 m/s without synaptic transmission or gap junctions, and this speed is not consistent with axonal conduction or ionic diffusion. The only explanation left is an electrical field effect. We tested the hypothesis that endogenous electric fields are sufficient to explain the propagation with in silico and in vitro experiments. Simulation results show that field effects alone can indeed mediate propagation across layers of neurons with speeds of 0.12 ± 0.09 m/s with pathological kinetics, and 0.11 ± 0.03 m/s with physiologic kinetics, both generating weak field amplitudes of ∼2-6 mV/mm. Further, the model predicted that propagation speed values are inversely proportional to the cell-to-cell distances, but do not significantly change with extracellular resistivity, membrane capacitance, or membrane resistance. In vitro recordings in mice hippocampi produced similar speeds (0.10 ± 0.03 m/s) and field amplitudes (2.5-5 mV/mm), and by applying a blocking field, the propagation speed was greatly reduced. Finally, osmolarity experiments confirmed the model's prediction that cell-to-cell distance inversely affects propagation speed. Together, these results show that despite their weak amplitude, electric fields can be solely responsible for spike propagation at ∼0.1 m/s. This phenomenon could be important to explain the slow propagation of epileptic activity and other normal propagations at similar speeds. Topics: Action Potentials; Animals; Calcium; Computer Simulation; Electromagnetic Fields; Electromagnetic Phenomena; Female; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Mice; Models, Neurological; Neurons; Osmolar Concentration; Piperidines; Potassium Channel Blockers | 2015 |
Design and synthesis of novel small molecule CCR2 antagonists: evaluation of 4-aminopiperidine derivatives.
A novel N-(2-oxo-2-(piperidin-4-ylamino)ethyl)-3-(trifluoromethyl)benzamide series of human CCR2 chemokine receptor antagonists was identified. With a pharmacophore model based on known CCR2 antagonists a new core scaffold was designed, analogues of it synthesized and structure–affinity relationship studies derived yielding a new high affinity CCR2 antagonist N-(2-((1-(4-(3-methoxyphenyl)cyclohexyl)piperidin-4-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. Topics: Chemokines; Humans; Molecular Structure; Piperidines; Receptors, CCR2; Structure-Activity Relationship | 2014 |
Disubstituted 1-aryl-4-aminopiperidine library synthesis using computational drug design and high-throughput batch and flow technologies.
A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times. Topics: Algorithms; Animals; ATP Binding Cassette Transporter, Subfamily B; Cell Line; Cell Membrane Permeability; Drug Design; High-Throughput Screening Assays; Humans; Microsomes; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Rats; Small Molecule Libraries; Solubility; Swine | 2013 |
Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses.
Efforts to study the development and function of the human cerebral cortex in health and disease have been limited by the availability of model systems. Extrapolating from our understanding of rodent cortical development, we have developed a robust, multistep process for human cortical development from pluripotent stem cells: directed differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells to cortical stem and progenitor cells, followed by an extended period of cortical neurogenesis, neuronal terminal differentiation to acquire mature electrophysiological properties, and functional excitatory synaptic network formation. We found that induction of cortical neuroepithelial stem cells from human ES cells and human iPS cells was dependent on retinoid signaling. Furthermore, human ES cell and iPS cell differentiation to cerebral cortex recapitulated in vivo development to generate all classes of cortical projection neurons in a fixed temporal order. This system enables functional studies of human cerebral cortex development and the generation of individual-specific cortical networks ex vivo for disease modeling and therapeutic purposes. Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Cell Differentiation; Cell Line; Cells, Cultured; Cerebral Cortex; Disks Large Homolog 4 Protein; Embryonic Stem Cells; Excitatory Amino Acid Antagonists; Fetus; Gene Expression Regulation, Developmental; Glutamic Acid; Humans; Intracellular Signaling Peptides and Proteins; Ki-67 Antigen; Membrane Proteins; Nerve Tissue Proteins; Neurogenesis; Patch-Clamp Techniques; Piperidines; Pluripotent Stem Cells; Potassium Channel Blockers; Retinoids; RNA, Messenger; Signal Transduction; Sodium Channel Blockers; Synapses; Synaptic Potentials; Tetrodotoxin; Time Factors; Transcription Factors | 2012 |
Hippocampus versus entorhinal cortex decoupling by an NR2 subunit-specific block of NMDA receptors in a rat in vitro model of temporal lobe epilepsy.
The role of N-methyl-D-aspartate receptors (NMDARs) in the generation and maintenance of epileptic seizures has been widely investigated, however, little is known of possible separate roles played by NMDARs that contain different NR2 subunits. A better comprehension of how distinct NMDARs subtypes participate in seizure generation and/or diffusion may lead to the development of more targeted pharmacologic strategies to treat epilepsy. Therefore, we have performed an electrophysiologic investigation using a multielectrode array device, on slices comprising entorhinal cortex (EC) and hippocampus, continuously perfused in a Mg(2+) -free medium, with added 4-aminopiridine (4AP; 10-15 μm). Two separate rhythmic patterns of interictal-like activity were generated in EC and hippocampus, with EC seizures entrained to those in CA3, so that a significant degree of cross-correlation occurred. Perfusion with the NR2A-containing NMDAR antagonist [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077; 50 nm) or Zn(2+) (200 nm), did not affect the rate of interictal-like events in EC and hippocampus; however, it significantly reduced their cross-correlation, causing a substantial decoupling of the two rhythm generators. The same effect was observed with (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate (Ro25-6981; 1 μm), when coapplied with a subthreshold dose of NVP-AAM077. Our results suggest that NR2 subunits may be crucial in entraining cortical networks, leading to recruitment of wider range oscillations during epilepsy. Therefore, a pharmacologic strategy directed onto NR2 subunits may help to limit seizure diffusion and recruitment of potentially entrained oscillatory networks. Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Dose-Response Relationship, Drug; Drug Interactions; Entorhinal Cortex; Excitatory Amino Acid Antagonists; Hippocampus; In Vitro Techniques; Neural Pathways; Patch-Clamp Techniques; Phenols; Piperidines; Potassium Channel Blockers; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate | 2012 |
Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS. Topics: Animals; Animals, Newborn; Calcium; Disease Models, Animal; Electric Stimulation; Excitatory Postsynaptic Potentials; Fragile X Mental Retardation Protein; Fragile X Syndrome; GABA Antagonists; Hippocampus; In Vitro Techniques; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Neural Inhibition; Neuronal Plasticity; Patch-Clamp Techniques; Phosphinic Acids; Piperidines; Potassium Channel Blockers; Presynaptic Terminals; Propanolamines; Sodium Channel Blockers; Synapses; Tetraethylammonium; Tetrodotoxin; Time Factors | 2011 |
Evaluation of a 4-aminopiperidine replacement in several series of CCR5 antagonists.
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists. Topics: CCR5 Receptor Antagonists; Drug Evaluation, Preclinical; Models, Molecular; Piperidines | 2010 |
Piperidinyl-nicotinamides as potent and selective somatostatin receptor subtype 5 antagonists.
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2' have been discovered as potent and selective SST5 antagonists. The activity (K(i)) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. Topics: Benzyl Compounds; Niacinamide; Piperidines; Receptors, Somatostatin; Stereoisomerism; Structure-Activity Relationship | 2010 |
Oligo(4-aminopiperidine-4-carboxylic acid): an unusual basic oligopeptide with an acid-induced helical conformation.
In sharp contrast with helical polypeptides carrying basic side chains, Api(8), a basic oligopeptide containing the non-natural achiral amino acid 4-aminopiperidine-4-carboxylic acid (Api), adopts a helical conformation only in acidic media. Alkaline titration of a protonated Api(8) oligomer appended with a leucine derivative at its N-terminus showed that disruption of its helical conformation occurs in a pH range of 7-10. NMR studies indicated that the piperidine groups in Api(8), when nonprotonated, possibly interact with the proximal amide protons in the peptide backbone and hamper the formation of the H-bonding network responsible for the helical conformation. The helical structure is induced not only by protonation but also by acylation of the piperidine groups. Topics: Magnetic Resonance Spectroscopy; Oligopeptides; Piperidines; Protein Conformation | 2010 |
Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.
Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.. glu-BAs aminopiperidine conjugates were synthesized. hASBT inhibition was measured as K(i). A CSP-SAR model was built using structural and physico-chemical descriptors and evaluated via cross-validation.. Twenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT, with K(i) ranging from 0.95 to 31.8 muM. Amidation of the piperidine nitrogen slightly decreased activity, while replacement by a carbon increased potency. Esterification of the glutamic acid linker had a minor impact, suggesting that a negative charge around C-24 is not required for binding. Three quantitative CSP-SAR models were developed. The best model (r (2) = 0.813, Q (2) = 0.726) included two descriptors: angle between 7-OH, alpha-substituent and centroid of rings B and C, and electrostatic contribution to the solvation free-energy. The model successfully distinguished between compounds with K(i) < 16muM and K(i) > 16muM. Models indicated that hydrophobicity, alpha substituent orientation, and partially compacted side chain conformation promote inhibitory potency. Qualitative CSP-SAR analysis indicated that the presence of an internal salt bridge, resulting in a locked conformation of the side chain, yielded weaker inhibitors.. Aminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed. Topics: Animals; Bile Acids and Salts; Cell Line; Computer Simulation; Dogs; Glutamic Acid; Humans; Kidney; Models, Molecular; Molecular Conformation; Organic Anion Transporters, Sodium-Dependent; Piperidines; Structure-Activity Relationship; Symporters | 2009 |
Antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives.
A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 microM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 microM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 microM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton. Topics: Animals; Antiprotozoal Agents; Cell Line; Eukaryota; Female; Inhibitory Concentration 50; Leishmania donovani; Mice; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Plasmodium falciparum; Rats; Trypanosoma brucei rhodesiense; Trypanosoma cruzi | 2009 |
The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat.
Oxaliplatin is a novel chemotherapeutic agent which is effective against advanced colorectal cancer, but at the same time causes severe neuropathy in the peripheral nerve fibres, affecting mainly the voltage-gated sodium (Na(+)) channels (VGNaCs), according to literature. In this study the effects of oxaliplatin on the peripheral myelinated nerve fibres (PMNFs) were investigated in vitro using the isolated sciatic nerve of the adult rat. The advantage of this nerve-preparation was that stable in amplitude evoked compound action potentials (CAP) were recorded for over 1000min. Incubation of the sciatic nerve fibres in 25, 100 and 500microM oxaliplatin, for 300-700min caused dramatic distortion of the waveform of the CAP, namely broadening the repolarization phase, repetitive firing and afterhyperpolarization (AHP), related to the malfunction of voltage-gated potassium (K(+)) channels (VGKCs). At a concentration of 5microM, oxaliplatin caused broadening of the repolarization phase of the CAP only, while the no observed effect concentration was estimated to be 1microM. These findings are indicative of severe effects of oxaliplatin on the VGKCs. In contrast, the amplitude and the rise-time of the depolarization of the CAP did not change significantly, a clear indication that the VGNaCs of the particular nerve preparation were not affected by oxaliplatin. The effects of oxaliplatin on the PMNFs were similar to those of 4-aminopyridine (4-AP), a classical antagonist of VGKCs. These similarities in the pattern of action between oxaliplatin and 4-AP combined with the fact that the effects of oxaliplatin were more pronounced and developed at lower concentrations suggest that oxaliplatin acts as a potent VGKCs antagonist. Topics: Anesthetics, Local; Animals; Antineoplastic Agents; Biophysical Phenomena; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Evoked Potentials; In Vitro Techniques; Lidocaine; Male; Organoplatinum Compounds; Oxaliplatin; Piperidines; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Rats; Rats, Wistar; Sciatic Nerve; Tetraethylammonium | 2008 |
Opposing inward and outward conductances regulate rebound discharges in olfactory mitral cells.
The olfactory bulb, a second-order sensory brain region, relays afferent input from olfactory receptor neurons to piriform cortex and other higher brain centers. Although large inhibitory postsynaptic potentials (IPSPs) are evident in in vivo intracellular recordings from mitral cells, the functional significance of these synaptic responses has not been defined. In many brain regions, IPSPs can function to either inhibit spiking by transiently suppressing activity or can evoke spiking directly by triggering rebound discharges. We used whole cell patch-clamp recordings from mitral cells in olfactory bulb slices to investigate the mechanisms by which IPSPs regulate mitral cell spike discharges. Mitral cells have unusual intrinsic membrane properties that support rebound spike generation in response to small-amplitude (3-5 mV) but not large-amplitude hyperpolarizing current injections or IPSPs. Rebound spiking occurring in mitral cells was dependent on recovery of subthreshold Na currents, and could be blocked by tetrodotoxin (TTX, 1 microM) or the subthreshold Na channel blocker riluzole (10 microM). Surprisingly, larger-amplitude hyperpolarizing stimuli impeded spike generation by recruiting a transient outward I(A)-like current that was sensitive to high concentrations of 4-aminopyridine and Ba. The interplay of voltage-gated subthreshold Na channels and transient outward current produces a narrow range of IPSP amplitudes that generates rebound spikes. We also found that subthreshold Na channels boost subthreshold excitatory stimuli to produce membrane voltages where granule-cell-mediated IPSPs can produce rebound spikes. These results demonstrate how the intrinsic membrane properties of mitral cells enable inhibitory inputs to bidirectionally control spike output from the olfactory bulb. Topics: Animals; Animals, Newborn; Drug Interactions; Electric Conductivity; Electric Stimulation; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Membrane Potentials; Neurons; Olfactory Bulb; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Riluzole; Sodium Channel Blockers; Tetrodotoxin | 2007 |
Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's disease.
Brain mononuclear phagocyte (perivascular macrophage and microglia, MG) inflammatory neurotoxins play a principal role in the pathogenesis of Parkinson's disease; chief among these are reactive oxygen species (ROS). We posit that aggregated, misfolded and oxidized alpha-synuclein (a major constituent of Lewy bodies), released or secreted from dying dopaminergic neurons, induces microglial ROS production that is regulated by ion channels and as such affects disease progression. To address this hypothesis, we performed patch clamp recordings of outward ionic currents in murine microglia and characterized their links to ROS production during alpha-synuclein stimulation. Aggregated nitrated alpha-synuclein induced ROS production in a dose-dependent manner that was inhibited by voltage-gated potassium current blockade, and to a more limited degree, by chloride current blockade. Interestingly, ROS produced in MG primed with tumor necrosis factor alpha and activated with phorbol myristate acetate was attenuated by voltage-gated potassium current blockade and more completely by chloride current blockade. In contrast, amyloid beta or cell membrane extract failed to induce microglial ROS production. Similar results were obtained using bone marrow-derived macrophages. The association of ROS production with specific plasma membrane ion currents provides a link between regulation of microglial ion transport and oxygen free radical production. Understanding these linkages may lead to novel therapeutics for Parkinson's disease where modulation of redox-related stress may slow disease progression. Topics: alpha-Synuclein; Animals; Animals, Newborn; Bone Marrow Cells; Cells, Cultured; Charybdotoxin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Gene Expression Regulation; Ion Channels; Macrophages; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Microglia; Neurotoxins; Patch-Clamp Techniques; Piperidines; Reactive Oxygen Species; Zinc | 2007 |
Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part III: synthesis of potent antagonists with alpha(v)beta3/alpha(IIb)beta3 dual activity and improved water solubility.
In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings. Topics: Animals; Aorta; Cell Adhesion; Crystallography, X-Ray; Drug Design; Humans; Integrin alphaVbeta3; Male; Mice; Models, Molecular; Molecular Structure; Myocytes, Smooth Muscle; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Conformation; Rats; Rats, Wistar; Solubility; Stereoisomerism; Structure-Activity Relationship; Vitronectin; Water | 2006 |
Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists.
We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. Topics: Animals; Aorta; Cell Adhesion; Crystallography, X-Ray; Drug Design; Humans; Integrin alphaVbeta3; Male; Mice; Models, Molecular; Molecular Structure; Myocytes, Smooth Muscle; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Rats; Rats, Wistar; Solubility; Stereoisomerism; Structure-Activity Relationship; Vitronectin; Water | 2006 |
Identification of substituted 4-aminopiperidines and 3-aminopyrrolidines as potent MCH-R1 antagonists for the treatment of obesity.
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM). Topics: Binding, Competitive; Drug Evaluation, Preclinical; Humans; Molecular Structure; Obesity; Piperidines; Pyrrolidines; Receptors, Somatostatin; Stereoisomerism; Structure-Activity Relationship | 2006 |
Potent 4-aminopiperidine based antimalarial agents.
A series of compounds with potent activity against a multi-drug-resistant strain of Plasmodium falciparum, the causative agent of the deadliest strain of malaria, is described. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their logD, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of compounds 9e and 10d, which showed good potency (IC(50)=75 nM and <60 nM, respectively, against Dd2), acceptable logD values, and reasonable metabolic stability. Topics: Animals; Antimalarials; Biological Assay; Fibroblasts; Hepatocytes; Humans; Inhibitory Concentration 50; Mice; Piperidines; Plasmodium falciparum; Structure-Activity Relationship | 2005 |
Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists.
4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N'-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors. Topics: Alkylation; Anti-HIV Agents; CCR5 Receptor Antagonists; Cell Line; HIV-1; Isonipecotic Acids; Organometallic Compounds; Piperidines; Structure-Activity Relationship | 2004 |
[The mechanisms of short-term forms of synaptic plasticity].
In experiments on the frog cutaneous pectoris muscle in cases of different external calcium concentrations, using extracellular recording technique, processes of facilitation and depression of transmitter release during the high-frequency stimulation were investigated. On the ground of experiments using intracellular mobile calcium buffers BAPTA-AM and EGTA-AM, it was proposed that at least two (low- and high-affinity) calcium-binding sites underlie the facilitation. Both the facilitation and the depression were accompanied by such transformations of underlied of nerve ending responses as changes of the third phase amplitude. Application of potassium channel blockers allowed us to reveal the significant contribution of changes of duration of the AP repolarisation phase and, accordingly, the changes of magnitude of calcium influx to development of facilitation and depression of transmitter release. It was also revealed that, during the high-frequency rhythmic stimulation, the increase of asynchrony of transmitter release leading to decrease of facilitation and increase of depression occurred. It was concluded that the forms of short-term synaptic plasticity--facilitation and depression, were caused by various presynaptic mechanisms: the increase of concentration of "local" and accumulation of "residual" calcium, the changes of calcium influx, increase of temporal course of secretion, the impairment of equilibrium between the depletion and restoration of mediator supply. Due to some of these processes and specific conditions of synapse functioning, the facilitation of the depression of transmitter release occurred. Topics: Action Potentials; Animals; Calcium; Egtazic Acid; Electric Stimulation; In Vitro Techniques; Neuromuscular Junction; Neuronal Plasticity; Peptides; Piperidines; Potassium Channel Blockers; Presynaptic Terminals; Rana ridibunda; Synaptic Transmission | 2004 |
4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs.
Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new compounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease. Topics: Amnesia; Animals; Avoidance Learning; Chemical Phenomena; Chemistry, Physical; Cognition; Dose-Response Relationship, Drug; Indicators and Reagents; Mice; Muscarinic Antagonists; Neurodegenerative Diseases; Nootropic Agents; Piperidines; Receptors, AMPA; Scopolamine; Structure-Activity Relationship | 2003 |
THE CHEMISTRY AND PHARMACOLOGY OF SOME 4-AMINOPIPERIDINES AND THEIR DERIVATIVES.
Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Central Nervous System; Chemistry, Pharmaceutical; Mice; Nervous System; Pharmacology; Piperidines; Research; Sympatholytics | 1964 |
Histamine antagonists; derivatives of 4-aminopiperidine.
Topics: Histamine Antagonists; Piperidines | 1948 |