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. Issue 7 (3rd March 2022) - Otte, Lorina
Abstract: 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 μ‐ and κ‐opioid receptors using a [ 35 S]‐GTPγS assay. The potencies of the investigated U‐opioids were lower than those of the reference compounds (μ‐opioid receptor: hydromorphone, fentanyl; κ‐opioid receptor: U‐69593, U‐50488). At the μ‐opioid receptor, U‐47700 showed the highest potency with an EC50 value of 111 nM, and at the κ‐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 μ‐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 κ‐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. Abstract : This study discusses in detail the structure activity relationship of eight U‐opioids with both the μ‐ and κ‐opioid receptors (MOR and KOR) using the [ 35 S]‐GTPγS assay and highlights structural advantages for a higher activity at these two receptors. U‐47700 showed the highest potency with an EC50 value of 111 nM, and at the κ‐opioid receptor, U‐51754 was found to be the most potent with an EC50 value of 120 nM.