Synthesis and SAR of novel GPR39 agonists and positive allosteric modulators.

Authors :: Burley R
Hewer RC
Teall M
Dickson L
Ossola B
Russell S
Bender C
Cheung T
Powell JAC
Xu X
Brice NL
Otter L
Arimont M
Kidd SL
Vidal D
Dale JW
Mervin L
Sore HF
Mateu N
Lakshminarayana N
Dawson LA
Carlton M
Bürli RW
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Apr 01; Vol. 61, pp. 128607. Date of Electronic Publication: 2022 Feb 03.
Publication Year :: 2022
Abstract: We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores. In vitro studies indicated that GPR39 agonism does not have a profound effect on neuroprotection.<br /> (Copyright © 2022 Elsevier Ltd. All rights reserved.)