Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists
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- 作者：Chunyang Jin ; cjin@rti.org ; Ann M. Decker ; Tiffany L. Langston
- 关键词：2-PCCA ; (1R ; 2R)-2-(pyridin-2-yl)cyclopropane carboxylic acid ((2S ; 3S)-2-amino-3-methylpentyl)-(4&prime ; -propylbiphenyl-4-yl)amide ; 2-AMPP ; (2S)-N-((1R)-2-amino-1-(4-(2-methyl-pentyloxy)phenyl)ethyl)-2-phenylpropanamide ; SAR ; structure activity relationship ; PPLS ; pre-prolactin leader sequence ; HA ; human influenza hemagglutinin ; HTRF ; homogeneous time resolved fluorescence ; MS ; mass spectroscopy ; TLC ; thin layer chromatography ; DIPEA ; N ; N-diisopropylethylamine ; DCM ; dichloromethane ; DEAD ; diethyl
- 刊名：Bioorganic & Medicinal Chemistry
- 出版年：2017
- 出版时间：15 January 2017
- 年：2017
- 卷：25
- 期：2
- 页码：805-812
- 全文大小：655 K
- 卷排序：25
文摘
The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.