Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor

Thomas O Schrader; Kym I Lorrain; Matthew R Nelli; Yu Xue; Yong Chen; Alexander Broadhead; Christopher Baccei; Austin Chen

doi:10.1016/j.bmcl.2025.130111

Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor

Bioorg Med Chem Lett. 2025 Jan 24:130111. doi: 10.1016/j.bmcl.2025.130111. Online ahead of print.

Authors

Thomas O Schrader¹, Kym I Lorrain², Matthew R Nelli², Yu Xue³, Yong Chen³, Alexander Broadhead², Christopher Baccei², Austin Chen²

Affiliations

¹ Contineum Therapeutics, 3565 General Atomics Court, Suite 200, San Diego, CA 92121, United States. Electronic address: tschrader@contineum-tx.com.
² Contineum Therapeutics, 3565 General Atomics Court, Suite 200, San Diego, CA 92121, United States.
³ Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, PR China.

PMID: 39864528
DOI: 10.1016/j.bmcl.2025.130111

Abstract

Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure-activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC₅₀ = 14 nM, 83 % E_max) that did not elicit a β-arrestin-2 recruitment functional response (E_max < 10 %). Compound 39 demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound 39 exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (K_i) assays. These findings highlight compound 39 and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.

Keywords: Biased agonist; Functionally-selective; GPCR; KOR; Kappa opioid receptor; Multiple sclerosis; Remyelination.