Currently available analgesic drugs, are not always efficacious, and pain control remains a major medical challenge in pain research. The activation of multiple pain-related targets is usually more effetive in relieving pain. In particular, increasing evidences suggest that a multitarget opioid ligands have the advantage of a better management of acute and chronic pain together with a lower incidence of side-effects.It has been demonstrated that in MOR/DOR ligands the DOR component gain importance when chronic pain develops (1, 2).We designed and synthesized a series of LR derivatives based on SAR studies on LP1, a MOR agonist/DOR antagonist benzomorphan-based compound (3-6), to obtain compounds with both MOR and DOR agonist profile. LR derivatives were tested by radiant competition binding assays in order to assess their affinity and selectivity on MOR, DOR and KOR. In comparison to LP1 new derivatives retained the MOR profile but showed an improved binding profile for DOR and KOR. In particular, the following compounds showed a relevant Ki profile of affinity versus opioid receptors: LR225 (KiMOR= 0,5 nM; KiDOR= 0,8 nM; KiMOR= 2,2 nM), LR235 (KiMOR= 1,08 nM; KiDOR= 6,6 nM; KiMOR= 15,22 nM) and LR224 (KiMOR= 2,47 nM; KiDOR= 9,6 nM; KiMOR= 7,3 nM). The functional profile of these compounds was evaluated by peripheral smooth muscle assays on isolated Guinea Pig Ileum and Mouse Vas Deferens. Results showed a balanced MOR/DOR agonist profile for LR224 (IC50= 89.2 nM and 10.8 nM) and LR225 (IC50= 9.9 nM and 11.8 nM) and a weak MOR and pronounced DOR agonist profile for LR235 (IC50= 141.4 nM and 4.4 nM). Tail flick test performed in mice was used to calculate the effective dose 50 (ED50) for each compound.: LR225 (ED50 of 1.4 mg/kg) and LR235, (ED50 of 1.0 mg/kg). Moreover, LR235 showed a long-lasting analgesic effect. LR compounds elicited analgesic effects at lower doses compared LP1 (ED50= 2.03 mg/Kg s.c.). Studies evaluating LR derivatives in persistent pain are in progress.

Dual MOR/DOR agonist benzomorphan-based compounds for pain relief

Aricò G.;Turnaturi R.;Arena E.;Prezzavento O;Pasquinucci L.;Parenti C.
2017

Abstract

Currently available analgesic drugs, are not always efficacious, and pain control remains a major medical challenge in pain research. The activation of multiple pain-related targets is usually more effetive in relieving pain. In particular, increasing evidences suggest that a multitarget opioid ligands have the advantage of a better management of acute and chronic pain together with a lower incidence of side-effects.It has been demonstrated that in MOR/DOR ligands the DOR component gain importance when chronic pain develops (1, 2).We designed and synthesized a series of LR derivatives based on SAR studies on LP1, a MOR agonist/DOR antagonist benzomorphan-based compound (3-6), to obtain compounds with both MOR and DOR agonist profile. LR derivatives were tested by radiant competition binding assays in order to assess their affinity and selectivity on MOR, DOR and KOR. In comparison to LP1 new derivatives retained the MOR profile but showed an improved binding profile for DOR and KOR. In particular, the following compounds showed a relevant Ki profile of affinity versus opioid receptors: LR225 (KiMOR= 0,5 nM; KiDOR= 0,8 nM; KiMOR= 2,2 nM), LR235 (KiMOR= 1,08 nM; KiDOR= 6,6 nM; KiMOR= 15,22 nM) and LR224 (KiMOR= 2,47 nM; KiDOR= 9,6 nM; KiMOR= 7,3 nM). The functional profile of these compounds was evaluated by peripheral smooth muscle assays on isolated Guinea Pig Ileum and Mouse Vas Deferens. Results showed a balanced MOR/DOR agonist profile for LR224 (IC50= 89.2 nM and 10.8 nM) and LR225 (IC50= 9.9 nM and 11.8 nM) and a weak MOR and pronounced DOR agonist profile for LR235 (IC50= 141.4 nM and 4.4 nM). Tail flick test performed in mice was used to calculate the effective dose 50 (ED50) for each compound.: LR225 (ED50 of 1.4 mg/kg) and LR235, (ED50 of 1.0 mg/kg). Moreover, LR235 showed a long-lasting analgesic effect. LR compounds elicited analgesic effects at lower doses compared LP1 (ED50= 2.03 mg/Kg s.c.). Studies evaluating LR derivatives in persistent pain are in progress.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/110118
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