Abstract
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 μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 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.
Highlights
Finding novel drugs for effective and safe management of severe and/or chronic pain poses a major challenge for modern medicinal chemistry and pharmacology
One that over the years has enjoyed a good deal of interest from the researchers is the development of multitarget analgesic (MTA) compounds [6,7]
Development of tolerance to morphine may be inhibited by some cannabinoid 1 receptor (CB1R) antagonists [52]. These facts prompted the development of MOR/CBR hybrid ligands made of peptide or alkaloid opioid fragments linked to CB1R or CB1R/CB2R pharmacophores [10,11,53]
Summary
Finding novel drugs for effective and safe management of severe and/or chronic pain poses a major challenge for modern medicinal chemistry and pharmacology. One that over the years has enjoyed a good deal of interest from the researchers is the development of multitarget analgesic (MTA) compounds [6,7] Substances of this type have significant affinity and activity at more than one molecular target involved in pain modulation. By simultaneous targeting of MOR and an additional receptor, a multifunctional analgesic could counteract the side effects directly or indirectly, in the latter case by improving efficacy and lowering the need for the activation of opioid pathways. In position 1, this ring is decorated with the phenethyl group (region B), while attached in position 4 is a nitrogen atom substituted with a phenyl ring (region C) and a propionyl group (region D) Over the years, this elementary structure has been thoroughly explored and numerous analogues of fentanyl (“fentanyls” or “fentalogues”) were synthesized for probing SAR of the 4-anilidopiperidine class of analgesics. That the structure of fentanyl (1.1) may be a good starting point for creating MTAs derives from (1) its pharmacological properties, (2) a relatively facile chemistry by which diverse analogues and functionalized derivatives can be accessed, (3) wealth of available structure-activity relationships (SAR) data
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