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Neurotherapeutics : the Journal of the... Apr 2010Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor... (Review)
Review
Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.
Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Neurotransmitter Agents; Piperazines; Quinazolines
PubMed: 20430315
DOI: 10.1016/j.nurt.2010.02.004 -
Journal of Enzyme Inhibition and... Dec 2023In this research, two novel series of dibenzo[]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported...
Design and synthesis of novel rigid dibenzo[]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.
In this research, two novel series of dibenzo[]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates () were evaluated for their ability to inhibit topoisomerase II, where was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, studies of showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate ().HighlightsTwo novel series of dibenzo[]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. was the most active anti-topo II congener (IC = 6.36 ± 0.36 µM). was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC = 13.05 ± 0.62 µM). studies of significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm compared to doxorubicin treatment.
Topics: Humans; Topoisomerase II Inhibitors; Structure-Activity Relationship; Intercalating Agents; Molecular Docking Simulation; Cell Line, Tumor; Azepines; Antineoplastic Agents; Doxorubicin; Leukemia; DNA; Cell Proliferation; Molecular Structure; Drug Screening Assays, Antitumor; DNA Topoisomerases, Type II
PubMed: 36629421
DOI: 10.1080/14756366.2022.2157825 -
IARC Monographs on the Evaluation of... 1996
Review
Topics: Animals; Azepines; Carcinogenicity Tests; Carcinogens; Humans; Tranquilizing Agents
PubMed: 9097123
DOI: No ID Found -
Cell Research Nov 2015BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the... (Review)
Review
BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the axis between sensitivity and resistance. Two recent papers published in Nature attempt to address this question in acute myeloid leukemia (AML) and independently identify the Wnt signaling pathway as a driver and biomarker of therapeutic resistance.
Topics: Animals; Azepines; Biomarkers, Tumor; Drug Resistance; Mice; Models, Animal; Neoplasms; Triazoles; Wnt Proteins; Wnt Signaling Pathway
PubMed: 26516144
DOI: 10.1038/cr.2015.127 -
Angewandte Chemie (International Ed. in... Dec 2017Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the...
Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of (R)- and (S)-5-methyl-6,7-dihydro-5H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework.
Topics: Azepines; Biocatalysis; Molecular Structure; Oxidoreductases Acting on CH-NH Group Donors; Stereoisomerism; Transaminases
PubMed: 29024400
DOI: 10.1002/anie.201708453 -
Journal of Medicinal Chemistry Dec 2020The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol...
The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.
Topics: Alkenes; Animals; Antineoplastic Agents; Antiprotozoal Agents; Apoptosis; Azepines; Benzylidene Compounds; Cell Line; Humans; Neoplasms; Oxidative Stress; Piperidones; Plasmodium falciparum; Proteasome Endopeptidase Complex; Receptors, Steroid; Ubiquitin
PubMed: 33146523
DOI: 10.1021/acs.jmedchem.0c00812 -
Current Opinion in Supportive and... Jun 2012We highlight the recent clinical trials for the management of acute and chronic migraine. (Review)
Review
PURPOSE OF REVIEW
We highlight the recent clinical trials for the management of acute and chronic migraine.
RECENT FINDINGS
In women with menstrual migraine, triptans seem to be well tolerated irrespective of whether or not patients are taking oestrogen-containing contraceptives or have comorbidities that indicate increased cardiovascular risk. The new acute drug, telcagepant, a calcitonin gene-related peptide (CGRP) antagonist, is safe for long-term use (up to 18 months) in migraine patients with stable coronary artery disease in whom the use of triptans is not advisable. From the pooled analysis of the two Phase III Research Evaluating Migraine Prophylaxis Therapy studies of onabotulinumtoxinA (BOTOX) in chronic migraineurs, it clearly emerged that efficacy increases overtime (up to 56 weeks) and paralleled self-perceived improvement in quality of life. Effectiveness was also observed in patients with severely disabling headaches, who met criteria for triptan abuse and were refractory to several prophylactic treatments. Finally, combination of preventive pharmacological agents with different action mechanisms may be the next frontier in therapeutic advancements for treating migraine.
SUMMARY
Although triptans are safe and well tolerated, CGRP antagonists may be an option for nonresponsive patients or those in whom the use of triptans is not advisable. New drugs and combinations of old therapeutic options may help patients with severe forms of headache.
Topics: Acute Disease; Azepines; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide Receptor Antagonists; Chronic Disease; Humans; Imidazoles; Migraine Disorders; Randomized Controlled Trials as Topic; Tryptamines
PubMed: 22406987
DOI: 10.1097/SPC.0b013e3283521dc3 -
Acta Crystallographica. Section C,... Apr 2010The title compound, C(26)H(45)N(3)O(8), is a bicyclic molecule; the seven-membered diazepane ring has a twisted-chair conformation and the six-membered morpholine ring...
The title compound, C(26)H(45)N(3)O(8), is a bicyclic molecule; the seven-membered diazepane ring has a twisted-chair conformation and the six-membered morpholine ring has a boat conformation.
Topics: Acetates; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Crystallography, X-Ray; Models, Molecular; Molecular Conformation; Molecular Structure; Morpholines; Stereoisomerism
PubMed: 20354302
DOI: 10.1107/S0108270109049361 -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Animals; Azepines; Humans; Male; Nuclear Proteins; Prostatic Neoplasms, Castration-Resistant; Transcription Factors; Triazoles
PubMed: 24905827
DOI: 10.4161/cc.29459 -
Marine Drugs Mar 2014Sponges corresponding to the Jaspidae family have proved to be a prolific source of bioactive natural products. Among these, the bengamides and the bengazoles stand out... (Review)
Review
Sponges corresponding to the Jaspidae family have proved to be a prolific source of bioactive natural products. Among these, the bengamides and the bengazoles stand out by virtue of their unprecedented molecular architectures and impressive biological profiles, including antitumor, antibiotic and anthelmintic properties. As a consequence, intense research activity has been devoted to these compounds from both chemical and biological standpoints. This review describes in detail the research into these classes of natural products and the benefits they offer in chemistry and biology.
Topics: Animals; Antineoplastic Agents; Azepines; Biological Products; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Lactones; Models, Molecular; Oxazoles; Porifera; Structure-Activity Relationship
PubMed: 24646945
DOI: 10.3390/md12031580