1421863-09-3Relevant 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.
Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II
Yu, Li-Fang,Eaton, J. Brek,Fedolak, Allison,Zhang, Han-Kun,Hanania, Taleen,Brunner, Dani,Lukas, Ronald J.,Kozikowski, Alan P.
, p. 9998 - 10009 (2013/01/16)
In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [3H]epibatidine binding studies together with functional assays based on 86Rb+ ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.
