The Design of Multitarget Ligands for Chronic and Neuropathic Pain

Abstract

In this review we have described the state-of-the-art of the multitarget approach for the control of pain. Several approaches adopted by different research groups and future perspectives have been discussed.

Cannabinoid receptors in osteoporosis and osteoporotic pain: a narrative update of review

“…Targeting again CB receptors and TRPV1 channel has been a novel therapeutic approach against chronic pain, and may be a strategy for osteoporosis and osteoporotic pain in the future. In addition, following the elucidation of glial cells in osteoporosis and osteoporotic pain through inflammation, it is possible to design multi‐target drugs against glia, CB receptors and TRPV1 channel for osteoporosis and osteoporotic pain …”

“…In addition, following the elucidation of glial cells in osteoporosis and osteoporotic pain through inflammation, [40][41][42] it is possible to design multi-target drugs against glia, CB receptors and TRPV1 channel for osteoporosis and osteoporotic pain. [48]…”

Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors

“…This way the pharmacokinetics and pharmacodynamics of the single drugs with substantially different absorption and partition properties will be the same, and a treatment method where the amount of the opioid component is subtherapeutic as compared to the administration without the cannabinoid can be applied. The strategy of combining GPCR ligands with various spacers to obtain multitargeting ligands is widely investigated with various success [76,77]. In our work JWH-018, a synthetic full agonist of CB receptors was covalently coupled with the semisynthetic opioid agonist oxycodone or with the enkephalin-related tetrapeptide agonist Tyr-D-Ala-Gly-Phe via spacers of different length and hydrophobicity.…”

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

“…Stimulated by the previously described SAR on fentanyl and its bivalent analogues, which reported no general rules for the effect of the substitution on the propionyl amide moiety, 5 we synthesised 12 novel 4-anilidopiperidine derivatives replacing the tertiary propyl-amide group in fentanyl, with different arylureas and aryl-carbamates found in several active FAAH and MAGL inhibitors with the intent to develop novel multitarget analgesics. 7,8 FAAH and MAGL are hydrolase enzymes, responsible of the endocannabinoid cleveage, and their inhibitors have shown to possess nociceptive effects in different pain models, as a consequence of the increased level of endocannabinoids 9,10 . A first series of compounds bearing the 4-anilidopiperidine scaffold on fentanyl was synthesised, and several substituted Oarylcarbamates (compounds OMDM584-OMDM589) have been used in place of the propylamide function.…”