Document Type

Article

Publication Date

7-2022

Journal Title or Book Title

ACS Chemical Neuroscience

Volume

13

Issue

13

Version

Publisher's PDF

Publisher's Statement

© 2022 The Authors. Published by American Chemical Society

DOI

10.1021/acschemneuro.2c00258

Abstract

The kappa agonist structure–activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced β2-arrestin recruitment and differential G-protein bias were observed for select analogues. To better understand the subtlety in receptor signaling, analogues were profiled as the resolved enantiomers. To determine in vivo target engagement, a subset of compounds was tested in mice for stimulation of serum prolactin, a neuroendocrine biomarker of KOR-agonist effects. Additional in vivo characterization included measurement of potential unwanted effects of kappa receptor activation such as sedation. These studies demonstrate a novel kappa receptor agonist scaffold with potential for G-protein signaling bias to probe in vivo pharmacology.

Related Pillar(s)

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Comments

Article is also availabe at https://doi.org/10.1021/acschemneuro.2c00258

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