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Journal of the American Chemical Society Feb 20052-aminopyridine and 2-aminobenzimidazole were chosen as structural analogues to substitute guanidinium groups in receptor molecules designed as phosphoryl transfer...
2-aminopyridine and 2-aminobenzimidazole were chosen as structural analogues to substitute guanidinium groups in receptor molecules designed as phosphoryl transfer catalysts. Shifting the pKa of the guanidinium analogues toward 7 was expected to raise catalytic activities in aqueous buffer. Although the pKa's of both heterocycles are similar (6.2 and 7.0), only 2-aminobenzimidazole led to active RNA cleavers. All cleavage assays were run with fluorescently labeled substrates and a DNA sequencer. RNase contaminations would degrade RNA enantioselectively. In contrast, achiral catalysts such as 9b and 10b necessarily induce identical cleavage patterns in RNA and its mirror image. This principle allowed us to safely rule out contamination effects in this study. The most active catalysts, tris(2-aminobenzimidazoles) 9b and 10b, were shown by fluorescence correlation spectroscopy (FCS) to aggregate with oligonucleotides. However, at very low concentrations the compounds are still active in the nonaggregated state. Conjugates of 10b with antisense oligonucleotides or RNA binding peptides, therefore, will be promising candidates as site specific artificial ribonucleases.
Topics: Aminopyridines; Base Sequence; Benzimidazoles; Catalysis; Guanidines; Hydrolysis; Kinetics; Nucleic Acid Conformation; RNA; Stereoisomerism
PubMed: 15713099
DOI: 10.1021/ja0443934 -
The Journal of Organic Chemistry Jan 2017Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo-...
Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands.
Topics: Alkynes; Aminopyridines; Catalysis; Cyanamide; Cycloaddition Reaction; Iron Compounds; Molecular Structure; Stereoisomerism
PubMed: 27957836
DOI: 10.1021/acs.joc.6b02374 -
Journal of Molecular Modeling Sep 2012Quantum-chemical calculations {DFT(B3LYP)/6-311+G(d,p)} were performed for all possible tautomers (aromatic and nonaromatic) of neutral 2- and 4-aminopyridines and their...
Quantum-chemical calculations {DFT(B3LYP)/6-311+G(d,p)} were performed for all possible tautomers (aromatic and nonaromatic) of neutral 2- and 4-aminopyridines and their oxidized and reduced forms. One-electron oxidation has no important effect on the tautomeric preference for 2-aminopyridine. The amine tautomer is favored. However, oxidation increases the stability of the imine NH tautomer, and its contribution in the tautomeric mixture cannot be neglected. In the case of 4-aminopyridine, one-electron oxidation increases the stability of both the amine and imine NH tautomers. Consequently, they possess very close energies. As major tautomers, they dictate the composition of the tautomeric mixture. The CH tautomers may be considered as very rare forms for both neutral and oxidized aminopyridines. A reverse situation takes place for the reduced forms of aminopyridines. One-electron reduction favors the C3 atom for the labile proton for both aminopyridines. This may partially explain the origin of the CH tautomers for the anionic states of nucleobases containing the exo NH(2) group.
Topics: 4-Aminopyridine; Aminopyridines; Aniline Compounds; Electrons; Entropy; Models, Molecular; Molecular Conformation; Oxidation-Reduction; Quantum Theory; Stereoisomerism
PubMed: 22585356
DOI: 10.1007/s00894-012-1446-8 -
The Journal of Pharmacology and... Jul 1983Aminopyridines, potent potassium channel blocking agents, were studied for their site of action and active form in the nerve membrane. Voltage clamped, internally...
Aminopyridines, potent potassium channel blocking agents, were studied for their site of action and active form in the nerve membrane. Voltage clamped, internally perfused squid giant axons were used. 3,4-Diaminopyridine, one of the most potent aminopyridine derivatives, blocked the potassium current much faster with internal application than with external application. When applied externally to the internally perfused axon, the onset of 3,4-diaminopyridine block was accelerated by suspending the internal flow. 4-Aminopyridine methiodide, a quaternary derivative of 4-aminopyridine, blocked the potassium current more effectively by internal application than by external application. These observations support the notion that aminopyridines act on a site more easily accessible from inside the nerve membrane than from outside. The block of the potassium current caused by internal 4-aminopyridine methiodide, similar to that caused by 4-aminopyridine or 3,4-diaminopyridine, was voltage-, time- and frequency-dependent, becoming less with longer and prolonged depolarization and with repetitive depolarizations. Low internal pH, which accelerated block re-establishment by the tertiary derivative, did not affect the quaternary derivative. Furthermore, when perfused internally at different total concentrations and different internal pH values, 2,3-diaminopyridine exhibited the same degree of block as long as the internally present cationic form concentration was kept constant. These results indicate that aminopyridines act in the cationic form.
Topics: 4-Aminopyridine; Amifampridine; Aminopyridines; Animals; Axons; Calcium Channel Blockers; Decapodiformes; Electrophysiology; Ion Channels; Potassium; Structure-Activity Relationship
PubMed: 6306223
DOI: No ID Found -
Angewandte Chemie (International Ed. in... May 2002
Topics: Aminopyridines; Catalysis; Ligands; Models, Molecular
PubMed: 19750652
DOI: 10.1002/1521-3773(20020503)41:9<1521::aid-anie1521>3.0.co;2-r -
The Journal of Pharmacy and Pharmacology Feb 1986The antagonism of pipecuronium- and vecuronium-induced neuromuscular blockade by 4-aminopyridine (4AP), 3,4-diaminopyridine (3,4AP) and 3-[(dimethylamino)-carbonyl]...
The antagonism of pipecuronium- and vecuronium-induced neuromuscular blockade by 4-aminopyridine (4AP), 3,4-diaminopyridine (3,4AP) and 3-[(dimethylamino)-carbonyl] amino-4-aminopyridine (LF14) were studied in anaesthetized cats during constant infusion of the relaxants. Aminopyridines were administered cumulatively at steady state 90% block level. The ED50 values of 4AP, 3,4AP and LF14 were 243, 106 and 254 micrograms kg-1 in pipecuronium, and 232, 195 and 235 micrograms kg-1 in vecuronium blockade. It has been assumed that in cats the anticurare effect of aminopyridines is mainly a result of K+ channel blockade on motor nerve terminals which enhances the evoked release of acetylcholine.
Topics: 4-Aminopyridine; Amifampridine; Aminopyridines; Androstane-3,17-diol; Animals; Cats; Male; Neuromuscular Nondepolarizing Agents; Pancuronium; Pipecuronium; Piperazines; Sciatic Nerve; Vecuronium Bromide
PubMed: 2870165
DOI: 10.1111/j.2042-7158.1986.tb04535.x -
Chemical Communications (Cambridge,... Sep 2002The title compounds are readily available by ring transformation of nitropyrimidione with active methylene compounds in the presence of ammonium acetate.
The title compounds are readily available by ring transformation of nitropyrimidione with active methylene compounds in the presence of ammonium acetate.
Topics: 4-Aminopyridine
PubMed: 12357829
DOI: 10.1039/b205510d -
Methods in Molecular Biology (Clifton,... 1993
Review
Topics: Aminopyridines; Carbohydrate Sequence; Carbohydrates; Chromatography; Humans; Molecular Sequence Data
PubMed: 8348245
DOI: 10.1385/0-89603-226-4:69 -
Biophysical Chemistry Jun 2003A functional model for the in vitro inactivation of voltage-dependent K(+) channels is developed. The model expresses the activity as a function of the aminopyridine...
A functional model for the in vitro inactivation of voltage-dependent K(+) channels is developed. The model expresses the activity as a function of the aminopyridine pK(a), the interaction energy with the receptor, and a quotient of partition functions. Molecular quantum similarity theory is introduced in the model to express the activity as a function of the principal components of the similarity matrix for a series of agonists. To validate the model, a set of five active (protonated) aminopyridines is considered: 2-aminopyridine, 3-aminopyridine, 4-aminoquinoleine, 4-aminopyridine, and 3,4-diaminopyridine. A regression analysis of the model gives good results for the variation of the observed activity with the overlap similarity index when pyridinic rings are superposed. The results support the validity of the model, and the hypothesis of a ligand-receptor entropy variation depending mainly on the nature of the ligand. In addition, the results suggest that the pyridinic ring must play an active role in the interaction with the receptor site. This interaction with the protonated pyridinic nitrogen can involve a cation-pi interaction or a donor hydrogen bond. The amine groups, at different relative positions of the pyridinic nitrogen, can form one or more hydrogen bonds due to the C(4) symmetry of the inner part of the pore in the K(+) channel.
Topics: Aminopyridines; Entropy; Hydrogen Bonding; Ligands; Linear Models; Models, Biological; Molecular Structure; Potassium Channels, Voltage-Gated; Protons
PubMed: 12878310
DOI: 10.1016/s0301-4622(03)00030-9 -
European Journal of Medicinal Chemistry Jan 2000Acetylcholine (Ach) enhancement, useful in the treatment of Alzheimer's disease (AD), may be obtained by means of ion channel modulators such as 4-aminopyridine (4-AP).... (Comparative Study)
Comparative Study
Acetylcholine (Ach) enhancement, useful in the treatment of Alzheimer's disease (AD), may be obtained by means of ion channel modulators such as 4-aminopyridine (4-AP). 4-AP is also the central ring of tacrine, the first drug approved for the treatment of AD. The synthesis and pharmacological activity of three 4-AP derivatives, prepared with the aim of improving their antiamnesic activity, is here described. In two of these compounds 4-AP is connected to 4-aminobutyric acid (GABA), whereas in the third it is connected to 2-indolinone, i.e., the skeleton of linopirdine, another Ach enhancing agent. The new compounds showed potent antiamnesic activity in comparison with piracetam.
Topics: 4-Aminopyridine; Alzheimer Disease; Aminopyridines; Amnesia; Animals; Avoidance Learning; Carbon Dioxide; Indoles; Male; Mice; Nootropic Agents; Piracetam
PubMed: 10733605
DOI: 10.1016/s0223-5234(00)00103-3