Structure Activity Relationships of Illicit Fentanyl Analogs

Abstract

Fentanyl is a highly potent and efficacious mu opioid receptor (MOR) agonist with significant abuse potential. More than 70% of opioid overdose deaths involve fentanyl or one of its analogs; recently the DEA announced that 2 in 5 counterfeit prescription pills contain a lethal dose of fentanyl. However, little is known about the novel fentanyl analogs (fentalogs) flooding the illicit drug market. It is presumed that these novel fentalogs are also potent, highly efficacious MOR agonists and they are driving the increase in opioid overdoses, but pharmacological data on these compounds are scarce. We have determined the affinity for and agonist activity of a library of novel fentanyl analogs in vitro. We found that structure greatly alters affinity and agonist activity; in this library, affinity at MOR ranged from 0.4 nM to almost 400 nM – fentanyl displays 1.6 nM affinity for MOR. Based on the data collected from this library, we have been able to construct structure‐activity relationships which may allow us to predict which fentalogs are potent agonists and are likely to carry significant abuse liability. Conversely, we have discovered new high affinity, low efficacy compounds which could be developed into novel rescue therapies.