1222136-77-7Relevant academic research and scientific papers
Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists
Zhang, Han-Kun,Eaton, J. Brek,Fedolak, Allison,Gunosewoyo, Hendra,Onajole, Oluseye K.,Brunner, Dani,Lukas, Ronald J.,Yu, Li-Fang,Kozikowski, Alan P.
, p. 689 - 697 (2016/09/23)
We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Kivalues of 0.5–51.4?nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50and IC50values of 15–50?nM) of the parent azetidine-containing compounds 3 and 4 in the86Rb+ion flux assays. In?vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCubeplatform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.
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 and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile
Zhang, Hankun,Tückmantel, Werner,Eaton, J. Brek,Yuen, Po-Wai,Yu, Li-Fang,Bajjuri, Krishna Mohan,Fedolak, Allison,Wang, Daguang,Ghavami, Afshin,Caldarone, Barbara,Paterson, Neil E.,Lowe, David A.,Brunner, Daniela,Lukas, Ronald J.,Kozikowski, Alan P.
, p. 717 - 724 (2012/03/27)
Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.
NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
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Page/Page column 134; 180-181, (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.
