Characterization of Pyrrolidinyl-hexahydro-pyranopiperazines as a Novel Kappa Opioid Receptor Agonist Scaffold

Authors

Brian Reed, Molloy UniversityFollow
Michael Miller
Mayako Michino
Eduardo R. Butelman
Ariel Ben-Ezra
Philip Pikus
Michelle Morochnik
Yuli Kim
Amy Ripka
Joseph Vacca
Mary Jeanne Kreek

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)

Study

Comments

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

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Reed, Brian; Miller, Michael; Michino, Mayako; Butelman, Eduardo R.; Ben-Ezra, Ariel; Pikus, Philip; Morochnik, Michelle; Kim, Yuli; Ripka, Amy; Vacca, Joseph; and Kreek, Mary Jeanne, "Characterization of Pyrrolidinyl-hexahydro-pyranopiperazines as a Novel Kappa Opioid Receptor Agonist Scaffold" (2022). Faculty Works: BCES (1999-2023). 47.
https://digitalcommons.molloy.edu/bces_fac/47