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

In 2009, new synthetic opioids appeared on the new psychoactive substances market. This class of new psychoactive substances generally poses a health risk due to the high affinity and potency of most of these compounds for the opioid receptors. It is known that overdoses can lead to respiratory depression and result in death. However, for many new synthetic opioids, data on toxicological and toxicokinetic properties are scarce. In the present study, eight U-opioids were investigated for their structure activity relationships at the mu- and kappa-opioid receptors using a [S-35]-GTP gamma S assay. The potencies of the investigated U-opioids were lower than those of the reference compounds (mu-opioid receptor: hydromorphone, fentanyl; kappa-opioid receptor: U-69593, U-50488). At the mu-opioid receptor, U-47700 showed the highest potency with an EC50 value of 111 nM, and at the kappa-opioid receptor, U-51754 was found to be the most potent compound with an EC50 value of 120 nM. The following structural features were advantageous for activating the mu-opioid receptor: two chlorine substituents in 3,4-position at the aromatic ring, the absence of the methylene group between the amide group and the aromatic ring, a methyl group at the amide nitrogen, and/or a dimethylamine residue at the amine nitrogen of the cyclohexane ring. Further, the following structural features were beneficial for kappa-opioid receptor activation: a methylene group between the amide group and the aromatic ring, a pyrrolidine residue at the amine nitrogen of the cyclohexane ring, a methyl group at the amide nitrogen, and/or a chlorine substitution at the 3,4-position of the aromatic ring.

Automated summary

In 2009, new synthetic opioids with high affinity and potency for opioid receptors appeared on the market. Data on toxicological and toxicokinetic properties of these compounds are scarce. This study investigated the structure-activity relationships of eight U-opioids at mu- and kappa-opioid receptors. The results showed that different structural features were advantageous for activating the two receptors.