1222136-80-2Relevant academic research and scientific papers
Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to α4β2-nicotinic acetylcholine receptors: An integrated approach to behaviorally active nicotinic ligands
Zhang, Han-Kun,Yu, Li-Fang,Kozikowski, Alan P.,Eaton, J. Brek,Lukas, Ronald J.,Nys, Mieke,Ulens, Chris,Mazzolari, Angelica,Vistoli, Giulio,Van Elk, Rene,Smit, August B.,Alexandrov, Vadim,Hanania, Taleen,Sabath, Emily,Fedolak, Allison,Brunner, Daniela
, p. 8028 - 8037,10 (2012)
Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2- nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.
NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
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, (2013/07/25)
The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.
Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. part II
Zhang, Han-Kun,Yu, Li-Fang,Eaton, J. Brek,Whiteaker, Paul,Onajole, Oluseye K.,Hanania, Taleen,Brunner, Daniela,Lukas, Ronald J.,Kozikowski, Alan P.
supporting information, p. 5495 - 5504 (2013/07/26)
A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.
NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
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Page/Page column 181, (2010/04/30)
The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.
