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Bioorganic & Medicinal Chemistry Letters Nov 2015To identify a new non-peptidyl BACE1 inhibitor, we focused on the aminopyridine structure, which binds to the active sites of BACE1. Synthesis of aminopyridine...
To identify a new non-peptidyl BACE1 inhibitor, we focused on the aminopyridine structure, which binds to the active sites of BACE1. Synthesis of aminopyridine derivatives and evaluation of inhibitory activity against rBACE1 are described. The 2-aminopyridine moiety and/or 3-methoxybenzaldehyde could be converted to terminal acetylene derivatives by the Sonogashira method. Sonogashira or Glaser cross-coupling reactions with the corresponding derivatives followed by hydrogenation could derive the designed compounds. Although inhibitory activities of the synthetic compounds against rBACE1 were weak, the aminopyridine motif has potential as a BACE1 inhibitor.
Topics: Aminopyridines; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Enzyme Inhibitors; Molecular Docking Simulation; Rats
PubMed: 26459211
DOI: 10.1016/j.bmcl.2015.10.007 -
Neurochemical Research Aug 1988The release of acetylcholine (ACh) elicited by electrical stimulation was investigated in rat brain cortical slices preloaded with 3H-choline. Decreasing the [Ca2+]o...
The release of acetylcholine (ACh) elicited by electrical stimulation was investigated in rat brain cortical slices preloaded with 3H-choline. Decreasing the [Ca2+]o from 2.5 to 0.3 mM caused a progressive reduction of the evoked release of ACh. 4-Aminopyridine (4AP) or LF14 [(1,1-dimethyl-3-(4-amino-3-pyridyl)], 4 x 10(-5) M doubled the evoked release of ACh when the [Ca2+]o was 2.5 mM and quadrupled it when it was 0.3 mM, to levels higher than those obtained with 2.5 mM [Ca2+]o alone. This indicates that both 4AP and LF14 decrease the Ca2+ requirements for the evoked release of ACh. The findings of this study indicate that LF14 may be suitable for the symptomatic treatment of senile dementia of Alzheimer's type, presumably caused by dysfunction of cholinergic transmission in the brain.
Topics: 4-Aminopyridine; Acetylcholine; Action Potentials; Aminopyridines; Animals; Calcium; Cerebral Cortex; Electric Stimulation; In Vitro Techniques; Male; Rats; Rats, Inbred Strains
PubMed: 2845287
DOI: 10.1007/BF00971599 -
ChemMedChem Oct 2012σ(2) Receptor research is receiving increasing interest with regard to the potential of σ(2) proteins as targets for tumor therapy and diagnosis. Nevertheless,...
σ(2) Receptor research is receiving increasing interest with regard to the potential of σ(2) proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the σ(2) receptor is far from conclusive. The paucity and modest affinity of known σ(2) antagonists represent one of the limitations to σ(2) receptor research. Previous studies of the high-affinity σ(2) agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 4 (PB28) suggested that a decrease in lipophilicity might lead to σ(2) ligands devoid of antiproliferative activity (potential σ(2) antagonists). With the aim of producing σ(2) receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both σ subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7σ(1)) were obtained. The effect on Ca(2+) mobilization was investigated for high-affinity compounds 18 and 4, which showed opposite effects. All of the data support the new 2-aminopyridines as high-affinity σ ligands with σ(2) antagonist and σ(1) agonist activity, and, despite the lack of significant σ(2) versus σ(1) selectivity, these novel compounds may be better tools for σ receptor research than the known low-affinity σ(2) antagonists.
Topics: Aminopyridines; Animals; Cell Line, Tumor; Cell Proliferation; Humans; Kinetics; Ligands; MCF-7 Cells; Mice; Receptors, sigma
PubMed: 22890883
DOI: 10.1002/cmdc.201200246 -
The Journal of Neuroscience : the... Jun 1988Cultured oligodendrocytes (OLGs) develop processes and form myelin following attachment to a substratum. We applied the whole-cell voltage-clamp technique to identify...
Cultured oligodendrocytes (OLGs) develop processes and form myelin following attachment to a substratum. We applied the whole-cell voltage-clamp technique to identify and characterize the ionic currents of OLGs in culture. Within 2 d after attachment, OLGs extended processes and began to express an outward current that represents a composite response of an inactivating/transient component and a non-inactivating component. The current had a reversal potential of -66 mV and was sensitive to potassium channel blockers. After 4-5 d in culture, the transient component was less prominent, often accompanied by an increase in noninactivating or steady-state outward current. In addition, there was an increase in inward rectifier current. Four of 7 cells that failed to develop processes exhibited only linear high-resistance membranes. We conclude that cultured OLGs express 3 voltage-gated potassium conductances: (1) a transient outward current, (2) a noninactivating outward current, and (3) an inward rectifier current. The sequential appearance of the several currents may relate, at least in part, to process formation.
Topics: 4-Aminopyridine; Aminopyridines; Animals; Cell Survival; Cells, Cultured; Cesium; Electrophoresis; Kinetics; Membrane Potentials; Neuroglia; Oligodendroglia; Potassium; Sheep; Tetraethylammonium; Tetraethylammonium Compounds
PubMed: 2838593
DOI: 10.1523/JNEUROSCI.08-06-02131.1988 -
British Journal of Anaesthesia Feb 1981
Topics: 4-Aminopyridine; Aminopyridines; Drug Interactions; Humans; Ketamine; Physostigmine
PubMed: 7470352
DOI: No ID Found -
Journal of Neurophysiology Feb 2016Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure...
Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K(+) channels due to myelin damage leads to conduction block, and K(+) channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K(+) channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K(+) channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases.
Topics: 4-Aminopyridine; Acrolein; Action Potentials; Aminopyridines; Animals; Male; Myelin Sheath; Neural Conduction; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 26581866
DOI: 10.1152/jn.00467.2015 -
The Journal of Organic Chemistry Mar 2011Tris(trimethylsilyl)silane and azobis(cyclohexanenitrile) promoted the easy intramolecular arylation of aryl bromopyridine carbamates through a radical [1,6] ipso...
Tris(trimethylsilyl)silane and azobis(cyclohexanenitrile) promoted the easy intramolecular arylation of aryl bromopyridine carbamates through a radical [1,6] ipso substitution process. These substrates showed a preference for this type of reaction over the alternative [1,7] addition. The results were rationalized by making use of quantum mechanical calculations and computer graphics.
Topics: Aminopyridines; Free Radicals; Models, Molecular; Molecular Structure; Quantum Theory; Stereoisomerism
PubMed: 21265527
DOI: 10.1021/jo102122h -
Critical Care Nurse 1985
Topics: Aminopyridines; Amrinone; Drug Interactions; Humans; Infusions, Parenteral
PubMed: 3845877
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Sep 2017Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a...
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.
Topics: Aminopyridines; Animals; Dogs; Dose-Response Relationship, Drug; Drug Design; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Madin Darby Canine Kidney Cells; Microsomes, Liver; Molecular Structure; Rats; Structure-Activity Relationship
PubMed: 28802631
DOI: 10.1016/j.bmcl.2017.07.072 -
Organic & Biomolecular Chemistry Feb 2013A facile and efficient synthetic route to multi-substituted 2-aminopyridines has been developed via a formal [5C + 1N] annulation of readily available...
A facile and efficient synthetic route to multi-substituted 2-aminopyridines has been developed via a formal [5C + 1N] annulation of readily available 2,4-pentadienenitriles with hydroxylamine (NH(2)OH) under very mild conditions, which involves sequential intermolecular aza-nucleophilic addition of hydroxylamine, intramolecular aza-cyclization, and dehydration reactions.
Topics: Aminopyridines; Hydroxylamine; Molecular Structure
PubMed: 23288150
DOI: 10.1039/c2ob27053f