Investigation of the μ and κ-opioid receptor activation by eight new synthetic opioids using the [35S]-GTPγS assay: U-47700, isopropyl U 47700, U-49900, U-47931E, N-methyl U-47931E, U-51754, U-48520 and U-48800

Since their first occurrence in 2008, a rapid increase of new psychoactive substances (NPS) on the recreational drug market has been observed. One class NPS are synthetic opioids, which poses health risk due to high affinity and potency most these compounds for opioid receptors. Four receptor subtypes known, mü-opioid (MOR), delta-opioid (DOR), kappa-opioid (KOR) nociceptin receptor, G protein-coupled receptors (GCPRs). MOR DOR agonists often express mood-enhancing euphoric properties. However, overdoses can lead respiratory depression result death. Nevertheless, many NPS, including data toxicological toxicokinetic properties scarce. The aim present study was investigate eight structurally closely related U-opioids (U-47700, isopropyl U-47700, U-49900, U-47931E, N-methyl U-48520, U-51754, U-48800) potential KOR activation, relative lack pharmacological U-opioids. [35S]-GTPγS assay, used activation is based exchange GDP with radiolabelled GTP. This one events GPCR-signal cascade. For each two respective well-studied were chosen as reference compounds: hydromorphone fentanyl MOR, U-69593 U-50488 KOR. Owing close structural similarity investigated U-compounds, structure activity relationships have also derived. prevalent compound this set, potent test set at an EC50 value 111 nM. had lower values 6.75 nM 24.9 nM, respectively, hence, being 16 4 times more than U-47700. At KOR, U-51754 substance out 120 U-50488, compounds, 5 29.3 24.8 respectively. studied be categorized into U-47700 group. It previously reported that group show higher binding affinities hence presence or absence methylene influence In general, our results good alignment affinities, confirming following features advantageous activating MOR: chlorine substituents 3,4-position aromatic ring, between amide methyl nitrogen, and/or dimethylamine residue amine nitrogen cyclohexane ring. Further, beneficial activation: pyrrolidine substitution While opioids considered conventional there some occurring market, less potent. Hence, performing studies important identify effect alterations understanding public health.