- Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
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Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
- Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
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p. 1349 - 1358
(2019/07/12)
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- New 'chemical probes' to examine the role of the hFPRL1 (or ALXR) receptor in inflammation
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We report the development of the novel N-substituted benzimidazole 11 as a potent and selective human formyl peptide receptor-like 1 (hFPRL1) agonist. This compound and its less active enantiomer 12 were identified as useful tools for studying receptor function in vitro.
- Frohn, Mike,Xu, Han,Zou, Xiaoming,Chang, Catherine,McElvaine, Michele,Plant, Matthew H.,Wong, Min,Tagari, Philip,Hungate, Randall,Buerli, Roland W.
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p. 6633 - 6637
(2008/03/18)
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- Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: Optimization of the 4-substituted piperidine
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In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.
- Burgey, Christopher S.,Stump, Craig A.,Nguyen, Diem N.,Deng, James Z.,Quigley, Amy G.,Norton, Beth R.,Bell, Ian M.,Mosser, Scott D.,Salvatore, Christopher A.,Rutledge, Ruth Z.,Kane, Stefanie A.,Koblan, Kenneth S.,Vacca, Joseph P.,Graham, Samuel L.,Williams, Theresa M.
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p. 5052 - 5056
(2007/10/03)
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- Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors
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A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
- Gustin, Darin J.,Sehon, Clark A.,Wei, Jianmei,Cai, Hui,Meduna, Steven P.,Khatuya, Haripada,Sun, Siquan,Gu, Yin,Jiang, Wen,Thurmond, Robin L.,Karlsson, Lars,Edwards, James P.
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p. 1687 - 1691
(2007/10/03)
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- Piperidines
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Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides substituted piperidines, and compositions containing these compounds. Also provided are methods using the compounds of the invention for the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrance of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a channel that includes a PN3 subunit.
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