Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a mu-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The nonopioid 'second' targets included proteins as diverse as imidazoline I-2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D-2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and sigma(1) receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.

Automated summary

The design of multitarget analgesics is a strategy in the search for safe and effective analgesic drugs. These drugs are intended to target multiple molecular targets involved in pain modulation. This article summarizes attempts to use fentanyl or its substructures as a scaffold for attaching fragments related to non-opioid receptors. The non-opioid targets include various proteins. The article reviews the chemistry, pharmacological properties, and structure-activity relationships of these attempts, and discusses future research directions.