期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 16, 页码 12397-12413出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01075
关键词
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资金
- National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01AA026820, R03AA029013]
- National Institutes of Health
This study identified a series of novel GPR88 agonists, with one showing high potency and suitability for studying the function of GPR88 in the brain.
The orphan receptor GPR88 has been implicated in a number of striatal-associated disorders, yet its endogenous ligand has not been discovered. We have previously reported that the amine functionality in the 2-AMPP-derived GPR88 agonists can be replaced with an amide (e.g., 4) without losing activity. Later, we have found that the amide can be replaced with a bioisosteric 1,3,4-oxadiazole with improved potency. Here, we report a further study of amide bioisosteric replacement with a variety of azoles containing three heteroatoms, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 1,4-disubstituted 1H-1,2,3-triazoles as GPR88 agonists. Collectively, our medicinal chemistry efforts have resulted in a potent, efficacious, and brain-penetrant GPR88 agonist 53 (cAMP EC50 = 14 nM), which is a suitable probe to study GPR88 functions in the brain.
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