Selective kappa opioid receptor (KOR) agonists are promising for treating pain and itch but often cause side effects like dysphoria and sedation. This study tested whether conditioned place aversion (CPA), a measure of dysphoria, is linked to KOR phosphorylation and internalization—markers of β-arrestin recruitment—in male mice. Using four KOR agonists at doses that maximally reduce pain and scratching, the authors found that U50,488H, MOM-SalB, and 42B, but not nalfurafine, induced KOR phosphorylation and internalization in brain regions. Yet, prior work showed that U50,488H and MOM-SalB cause CPA, while nalfurafine and 42B do not. These results indicate no connection between CPA and these β-arrestin-related processes.
Salvinorin A, the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Researchers synthesized a series of C-2 halogenated analogs of salvinorin A as molecular probes to investigate the binding pocket at the C-2 position, particularly the effects of α versus β configuration. Binding and functional studies showed that β isomers generally bind better than α isomers, except for iodinated analogs. None of the C-2 halogenated analogs improved KOPR binding affinity compared to the parent compound. Functional assays characterized one analog, 6b, as a partial agonist with a maximum effect of 46% of the full agonist U50,488H at 250 nM. Affinity to the kappa receptor increased with atomic radius (I>Br>Cl>F), consistent with halogen bonding interactions.
Salvinorin A, the main active ingredient of Salvia divinorum, is a potent and selective kappa-opioid receptor agonist. A series of C-12 triazole analogs and an oxadiazole analog were synthesized and tested for binding affinity at kappa, mu, and delta opioid receptors. Surprisingly, all triazole analogs showed negligible binding affinity at opioid receptors, and the oxadiazole analog, previously reported as a mu and kappa opioid receptor antagonist, exhibited very low affinities and no antagonism in the binding assays. These results suggest that electronic factors affecting either the electron density of a hydrogen bond acceptor at C-12 or hydrophobic interactions between the C-12 moiety and the kappa-opioid receptor are critical for C-12 analog affinity.