“We confirmed that conolidine binds to the newly identified opioid receptor ACKR3, while showing no affinity for the other four classical opioid receptors. By doing so, conolidine blocks ACKR3 and prevents it from trapping the naturally secreted opioids, which in turn increases their availability for interacting with classical receptors. We believe that this molecular mechanism is at the basis of the beneficial effects of this traditionally used medicine on pain relief”, lead author Martyna Szpakowska, a scientist within the LIH Immuno-Pharmacology and Interactomics group said in a press release.
Scientists also developed a modified version of conolidine called RTI-5152-12. It binds only to ACKR3 with greater affinity. Scientists hypothesize this increases opioid peptides levels that bind to classical opioid receptors. That leads to increased painkilling activity. In December 2020, the researchers filed a joint patent application.
“The discovery of ACKR3 as a target of conolidine further emphasises the role of this newly discovered receptor in modulating the opioid system and, consequently, in regulating our perception of pain,” said corresponding author Dr. Andy Chevigné, head of Immuno-Pharmacology and Interactomics at LIH.
“Our findings could also mean that conolidine, and potentially also its synthetic analogues, could carry new hope for the treatment of chronic pain and depression, particularly given the fact that conolidine was reported to trigger fewer of the detrimental side-effects — namely addiction, tolerance and respiratory problems — associated with commonly used opioid drugs like morphine and fentanyl.”
Dr. Ojas Namjoshi, co-corresponding author of the publication and lead scientist on the study at RTI said the research “could therefore set the basis for the development of a new class of drugs with alternative mechanism of action, thereby contributing to tackling the public health crisis linked to the increasing misuse of and addiction to opioid drugs.”