- DETECTION OF 2,5-DIMETHYLENE-2,5-DIHYDROTHIOPHENE AND THIOPHENORADIALENE
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The reactive species 2,5-dimethylene-2,5-dihydrothiophene and thiophenoradialene have been detected for the first time.The method of HCl elimination has proved to be a generally applicable method for generating heterocyclic xylylenes and radialenes.
- Muenzel, Norbert,Kesper, Karl,Schweig, Armin,Specht, Harald
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Read Online
- Novel M2-selective, Gi-biased agonists of muscarinic acetylcholine receptors
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Background and Purpose: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. Experimental Approach: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M2 receptors was modelled in silico. Key Results: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. Conclusions and Implications: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.
- Randáková, Alena,Nelic, Dominik,Ungerová, Dana,Nwokoye, Peter,Su, Qiwen,Dole?al, Vladimír,El-Fakahany, Esam E.,Boulos, John,Jakubík, Jan
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supporting information
p. 2073 - 2089
(2020/02/18)
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- MUSCARINIC AGONISTS AS NON-STEROIDAL AND NON-OPIOID ANALGESICS AND METHODS OF USE THEREOF
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Novel Gi/o-biased muscarinic agonists selectively activate only one specific signaling pathway and are novel pharmacophores for development of new painkillers (analgesics). Methods of making and using these agonists are also described.
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Paragraph 0060; 0073; 0076; 00106
(2020/09/19)
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- SUBSTITUTED HETEROAROMATIC PYRAZOLO-PYRIDINES AND THEIR USE AS GLUN2B RECEPTOR MODULATORS
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Substituted Pyrazolo-pyridines as GluN2B receptor ligands. Such compounds may be used in GluN2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by GluN2B receptor activity.
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Page/Page column 68; 73
(2020/12/30)
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- Palladium-catalyzed regioselective allylation of five-membered heteroarenes with allyltributylstannane
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Palladium-catalyzed allylation reactions of 2-(chloromethyl)thiophenes, 2-(chloromethyl)furans, and N-protected 2-(chloromethyl)-1H-pyrroles with allyltributylstannane were described in this study. This type of allylation reaction regioselectively occurred on the heteroarene rings to produce allylated dearomatization products or allylated heteroarenes with satisfactory yields.
- Zhang, Sheng,Yu, Xiaoqiang,Feng, Xiujuan,Yamamoto, Yoshinori,Bao, Ming
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p. 3842 - 3845
(2015/03/30)
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- Synthesis of N-substituted piperidine salts as potential muscarinic ligands for Alzheimer's applications
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Several heterocyclic N-piperidine substituted salts were synthesized that were found to inhibit the specific binding of the antagonist [3H] quinuclidinyl benzilate in radioligand muscarinic binding assays ( 3H-QNB) in bioassays. One
- Boulos, John,Jakubik, Jan,Randakova, Alena,Avila, Cristina
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p. 1363 - 1367
(2014/01/06)
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- NOVEL HETEROCYCLIC ACRYLAMIDES AND THEIR USE AS PHARMACEUTICALS
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The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.
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Page/Page column 95-96
(2011/06/19)
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- Synthesis and Properties of 2,5-Dimethylnaphthodithiophene as a New Electron Donor
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A new synthesis of 2,5-dimethylnaphthodithiophene 12 and its redox properties are reported.
- Moradpour, Alec
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