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

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/Gprotein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced ??2arrestin 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.

Automated summary

In this study, a novel kappa receptor agonist scaffold was developed and the modulation of receptor activity and complex function was demonstrated by altering the functional groups in the compounds. This research is important for understanding the intricacies of receptor signaling and developing biased drugs.