N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity.
N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity.
复制标题
DOI：
10.1021/jm200288r
复制
发表时间：
2011-05-26
影响因子：
7.3
通讯作者：
Newman AH
中科院分区：
文献类型：
--
作者：
Banala AK;Levy BA;Khatri SS;Furman CA;Roof RA;Mishra Y;Griffin SA;Sibley DR;Luedtke RR;Newman AH
N-(3-fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)-butyl)-aryl carboxamides were prepared and evaluated for binding and function at dopamine D3 (D3R) and D2 receptors (D2R). In this series, we discovered some of the most D3R selective compounds reported to date, (e.g. 8d and 8j >1000-fold D3R-selective over D2R.) In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold (e.g. D3RKi for 15b = 393 v. for 8j = 2.6 nM) resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.
登录
查看更多内容
影响因子：
7.3
作者：
Newman AH;Grundt P;Cyriac G;Deschamps JR;Taylor M;Kumar R;Ho D;Luedtke RR
通讯作者：
Luedtke RR
影响因子：
3.6
作者：
Lan, HX;DuRand, CJ;Neve, KA
通讯作者：
Neve, KA
DOI：
10.1124/jpet.110.167619
发表时间：
2010-08-10
影响因子：
3.5
作者：
Achat-Mendes, Cindy;Grundt, Peter;Spealman, Roger D.
通讯作者：
Spealman, Roger D.
影响因子：
2.7
作者：
Grundt, Peter;Husband, Sarah Little Jane;Newman, Amy Hauck
通讯作者：
Newman, Amy Hauck
影响因子：
7.3
作者：
Ehrlich, Katharina;Gotz, Angela;Gmeiner, Peter
通讯作者：
Gmeiner, Peter