Millions of people worldwide suffer from a specific form of chronic pain conditions which significantly impairs daily activities, including work. Standard treatments, including opioids and anticonvulsants, are effective treatments. However, these medications possess severe side-effects (e.g., tolerance, respiratory depression, sedation), which mitigate their therapeutic benefits. Therefore, the development of safer painkillers, which might exert their activity through alternative targets, such as sigma receptors (σRs) [1-2], is still a medical need to meet. In an attempt to develop novel non-opioid drugs to treat neuropathic pain, we designed and synthesized a new set of 6-substituted-2(3H)-benzothiazolones, and 6-substituted-2(3H)-benzoxazolones as σ receptor ligands. Two of the new highaffinity σ1 receptor ligands 3-(2-(azepan-1-yl)ethyl)-6-benzylbenzo[d]thiazol- 2(3H)-one (MCI 77, Ki σ1 = 5.41 nM) and 3-(2-(azepan-1-yl)ethyl)-6-(3- fluorobenzyl)benzo[d]oxazol-2(3H)-one (MCI 92, Ki σ1 = 2.01 nM), were selected for in vivo pharmacological evaluation. As a result, both analogs showed antineuropathic pain effect in mice (45 mg/kg, i.p.). In addition, no locomotor impairment was observed at the tested dose. Overall, these preliminary data are indicative of the potential for further drug development and optimization of this set of compounds.

Novel benzothiazolones and benzoxazolones-based σ receptor ligands: synthesis and preliminary pharmacological evaluation against allodynia

Intagliata Sebastiano
Primo
2019-01-01

Abstract

Millions of people worldwide suffer from a specific form of chronic pain conditions which significantly impairs daily activities, including work. Standard treatments, including opioids and anticonvulsants, are effective treatments. However, these medications possess severe side-effects (e.g., tolerance, respiratory depression, sedation), which mitigate their therapeutic benefits. Therefore, the development of safer painkillers, which might exert their activity through alternative targets, such as sigma receptors (σRs) [1-2], is still a medical need to meet. In an attempt to develop novel non-opioid drugs to treat neuropathic pain, we designed and synthesized a new set of 6-substituted-2(3H)-benzothiazolones, and 6-substituted-2(3H)-benzoxazolones as σ receptor ligands. Two of the new highaffinity σ1 receptor ligands 3-(2-(azepan-1-yl)ethyl)-6-benzylbenzo[d]thiazol- 2(3H)-one (MCI 77, Ki σ1 = 5.41 nM) and 3-(2-(azepan-1-yl)ethyl)-6-(3- fluorobenzyl)benzo[d]oxazol-2(3H)-one (MCI 92, Ki σ1 = 2.01 nM), were selected for in vivo pharmacological evaluation. As a result, both analogs showed antineuropathic pain effect in mice (45 mg/kg, i.p.). In addition, no locomotor impairment was observed at the tested dose. Overall, these preliminary data are indicative of the potential for further drug development and optimization of this set of compounds.
2019
978-88-94952-15-5
chronic pain, non opioid drugs, benzothiazolones, benzoxazolones, σ receptor ligands
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/551195
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