Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Abstract

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both m and d-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation.

Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor

“…The resulting compounds 23-26 (Figure 3) maintained the same central benzoylpiperidine scaffold and derived from the combination of different substituents in the two terminal portions of the parent compound 9 and they were synthesized accordingly. -d, 11a-d, 12a-d, 13a-d) and in the benzoyl (14)(15)(16)(17)(18)(19)(20)(21)(22) portions. Chemistry.…”

“…7,8 Several studies indicate the therapeutic potential of selective FAAH and MAGL inhibitors in several disease models of inflammation, pain, anxiety and other neuroinflammatory diseases. [9][10][11][12][13][14][15][16] The inhibition of eCBs degradation represents a promising pharmacological strategy to activate the ECS limiting the potential side effects associated with direct receptor agonists. 7,17,18 Many MAGL inhibitors were published 19 and patented 20 and some representative compounds are reported in Figure 1; however, most MAGL inhibitors reported to date in the literature are characterized by an irreversible binding mode.…”

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

“…Researchers of various groups reported novel analogues, including those of norsufentanil [10], carfentanil amides [11] or acrylic derivatives [12]. Fentanyl scaffold has also been used in the design of bivalent (multitarget) compounds to create mixed μ-/δ-OR ligands [13,14,15], or molecules joining even more distant pharmacophores like opioid receptor agonist and FAAH/MAGL hydrolases inhibitors [16], or opioid and dopamine receptors D2/D3 ligands [17]. Most excitingly, fentanyl has its place also in the most up-to-date trends of pain pharmacology that is in the research on biased μOR agonists which holds promise for finding strong analgesics without adverse effects.…”

Synthesis and In Vitro Evaluation of Caffeoylquinic Acid Derivatives as Potential Hypolipidemic Agents

“…These above results suggest that derivatives 3d , 3g , 4c, and 4d may be a promising therapeutic candidate as potential hypolipidemic agents. Further studies to design the derivatives of chlorogenic acid coupled with naturally occurring kinds of amino acids, as well as to explore the mechanism of action of this novel class of compounds is, planned to start in our group in the near future [21,22,23].…”