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

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.

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

“…We designed new MTDLs using the “merging approach″ , by combining the pharmacophore of the AChE-I donepezil with that of the previously described potent thiophene-based CB2R agonist, which we named COR783, to maximize the degree of skeletal overlap and generate molecules with acceptable physicochemical properties (Figure ), such as a lower lipophilicity. The newly developed molecules, which contain the basic benzylamine moiety (p K a approximately 9.0) of donepezil and are protonated at neutral physiological pH, should interact better with the active site of AChE, while, on the other hand, they should be less lipophilic than COR783.…”