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Results for “Azepines”

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At least 127 records · Page 7Linked to original sources
PubMed1994

Resolution of 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4yl)-1(2H)-phthalazi none enantiomers in plasma with frit-FAB LC-MS using a conalbumin column.

A new column-switching method for analysis of drug enantiomers in plasma has been developed with liquid chromatography-frit fast atom bombardment mass spectrometry in combination with a chiral resolution column, which consists of conalbumin (egg-white glycoprotein) immobilized on silica gel and can be used in the reversed-phase separation mode. This method makes it possible to inject a large volume of deproteinized plasma and obtain resolution of drug enantiomers with high sensitivity. The optimum mobile phase, including a non-volatile buffer such as phosphate buffer, for separation of drugs from a large amount of endogenous compounds can be used, because of inclusion of a trapping column with a desalting function. This method is very simple and rapid, and should be very powerful in studies requiring high-sensitivity analysis with chiral separation of drugs from biological samples such as plasma.

Chromatography, High Pressure Liquid↗
PubMed1997

Further definition of the D1 dopamine receptor pharmacophore: synthesis of trans-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphth[2,1-b]azepines as rigid analogues of beta-phenyldopamine.

In an effort to define further the active geometry of the beta-phenyldopamine pharmacophore of certain dopamine D1 agonists, the title compounds have been synthesized as conformationally restricted homologues of the potent benzophenanthridine dopamine D1 agonist dihydrexidine 4a. The dihydroxy secondary amine 5b was evaluated as a potential agonist, whereas the N-methyl compounds 5a and 5c were hypothesized to be antagonists. Surprisingly, none of the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the low-energy conformations of these molecules shows that the pendant phenyl ring of 5b is twisted about 28 degrees relative to that of the corresponding ring of 4a. Further, the additional methylene used to expand the C ring of 5b projects toward the alpha face of the molecule, perhaps suggesting that steric protrusion in this region of the molecule is not tolerated. Finally, the phenethylamine fragment incorporated into these molecules deviates about 30 degrees from the antiperiplanar conformation postulated to be necessary for agonist activity. On the other hand, the potential antagonist molecules 5a and 5c were compared with the dopamine D1 antagonist SCH 39166 2. The conformations of the former two structures differ quite dramatically from that of 2. The most notable differences lie in the relative orientations of the pendant phenyl rings in the two series, as well as the fact that the ethylamine fragment in 2 approximates a gauche conformation, while the comparable orientation in 5a and 5c more nearly approaches an antiperiplanar conformation. These findings will be used to refine further the model of the dopamine D1 agonist receptor that we have previously developed.

Animals↗
PubMed2004

Rhodium(I)-catalyzed ene-allene carbocyclization strategy for the formation of azepines and oxepines.

[reaction: see text] A novel strategy for the preparation of seven-membered heterocyclic compounds has been realized. Treatment of ene-allene 1 with a catalytic quantity of rhodium biscarbonyl chloride dimer affords the cyclization product 2 in moderate to high yields. The scope and limitations of this new method are currently under investigation, and the results obtained to date are discussed within.

Journal Article↗
PubMed2002

Effects of carbamazepine and novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives on synaptic transmission in rat hippocampal slices.

The effects of carbamazepine on synaptic transmission in rat hippocampal slices were compared with those of two novel analogues (BIA2-093 and BIA2-024) with equivalent anticonvulsant efficacy but with fewer side effects. Carbamazepine (10-1000 microM) inhibited in a concentration-dependent manner the field excitatory postsynaptic potential (fPSP) response, with an EC50 of 263 microM, and also attenuated the presynaptic volley with a similar EC50 value. Carbamazepine was more potent to inhibit the NMDA receptor component of the fPSP (fPSPNMDA), with an EC50 of 160 microM. BIA2-093 and BIA2-024 were nearly equipotent with carbamazepine to inhibit synaptic transmission, and displayed similar potency to inhibit the fPSP (EC50 of 145 microM and 205 microM) and fPSPNMDA responses (EC50 of 198 microM and 206 microM). As with carbamazepine, BIA2-093 and BIA2-024 also attenuated the presynaptic volley with EC50 values ranging from 142 to 322 microM. These results indicate that carbamazepine and its analogues mostly inhibit synaptic transmission through inhibition of conduction, although carbamazepine, but not BIA2-093 and BIA2-024, may also depress NMDA receptor-mediated responses.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Identification of benz(othi)azepine-binding regions within L-type calcium channel alpha1 subunits.

To identify the binding domain for diltiazem-like Ca2+ antagonists on L-type Ca2+ channel alpha1 subunits we synthesized the benzazepine [3H]benziazem as a novel photoaffinity probe. [3H]Benziazem reversibly labeled the benzothiazepine (BTZ)-binding domain of partially purified skeletal muscle Ca2+ channels with high affinity (Kd = 12 nM) and photoincorporated into its binding domain with high yield (>66%). Antibody mapping of proteolytic labeled fragments revealed specific labeling of regions associated with transmembrane segments S6 in repeats III and IV. More than 50% of the labeling was found in the tryptic fragment alanine 1023-lysine 1077 containing IIIS6 together with extracellular and intracellular amino acid residues. The remaining labeling was identified in a second site comprising segment S6 in repeat IV and adjacent residues. Unlike for dihydropyridines, no labeling was observed in the connecting IIIS5-IIIS6 linker. The [3H]benziazem photolabeled regions must be in close contact to the drug molecule when bound to the channel. We propose that the determinants for high affinity BTZ binding are located within or in close proximity to segments IIIS6 and/or IVS6. Therefore the binding domain for BTZs, like for the other main classes of Ca2+ antagonists, must be located in close proximity to pore-forming regions of the channel.

Affinity Labels↗
PubMed1994

[Studies on zwitter-ionization of drugs. III. Synthesis and pharmacological activities of N-alkylcarboxylic acid derivatives of 1,2,3,4,10,14b-Hexahydrodibenzo[c,f]-pyrazino[1,2-a]azepine and 2,3,4,9-tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2-c]pyridine].

The N-alkylcarboxylic acids of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-alpha]az epi ne (6a) and 2,3,4,9-tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2- c]pyridine (6b) were synthesized and examined for pharmacological activities in vitro: an inhibitory effect on the monoamine [noradrenaline (NA) and 5-hydroxytryptamine (5-HT)] uptake into the rat crude synaptosome, an inhibitory effect on the 5-HT- and NA-induced contraction in the isolated rabbit aorta and on the histamine- and acetylcholine-induced contraction in the isolated guinea-pig ileum, and binding affinity for alpha 2-adrenoceptor and D2-receptor. The in vitro tests indicated that zwitter-ionization was capable of maintaining antihistaminic activity while greatly reducing other pharmacological activities such as effects on central nervous system. 3-[2,3,4,9-Tetrahydro-1H-dibenzo[3,4: 6,7]cyclohepta[1,2- c]pyridin-2-yl]propionic acid (6b-2), selected as a candidate antiallergic agent having equally potent activities in rats and guinea-pigs, exhibited strong inhibitory effects on 48 h homologous passive cutaneous anaphylaxis (PCA) in rats (ED50 = 0.012 mg/kg, p.o.) and on histamine-induced bronchoconstriction in anesthetized guinea-pigs (ED50 = 0.0088 mg/kg, p.o.).

Animals↗