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

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.