Pharmacology of newly identified nitazene variants reveals structural determinants of affinity, potency, selectivity for mu opioid receptors

Nitazenes, a group of synthetic benzimidazole opioids, are a growing public health threat that have been linked to hundreds of deaths within the last five years. New nitazenes are discovered each year in drug samples and toxicology specimens, necessitating rapid pharmacological characterization. We characterized thirteen nitazenes identified by DEA as chemicals of concern, some that have not been previously characterized. We found that most were very high affinity and potency agonists at the mu opioid receptor (MOR) with very high selectivity for MOR versus other opioid receptors. While bulky benzyl substitutions and a lengthier linker reduced affinity and potency for MOR, the majority of nitazenes tested nonetheless exhibited high-to-very high MOR affinity, potency, and selectivity – often greater than that of fentanyl. Three of the nitazenes exhibited a novel pharmacological pattern, with lower selectivity for MOR versus the kappa opioid receptor (KOR), and with a pharmacological profile that more closely resembles morphine than fentanyl. These findings further delineate the chemical determinants of nitazene pharmacology and identify three of the least MOR-selective nitazenes to date.