Synthesis and Biological Evaluation of Novel σ₁ Receptor Ligands for Treating Neuropathic Pain: 6‑Hydroxypyridazinones

By use of the 6-hydroxypyridazinone framework, a new series of potent σ₁ receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ₁ receptor affinity (<i>K</i>_i σ₁ = 1.4 nM) and excellent selectivity over not only σ₂ receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)­propoxy)­pyridazin-3­(2<i>H</i>)-one (compound <b>54</b>). Compound <b>54</b> exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound <b>54</b> was evaluated using phenytoin and indicated that the compound was a σ₁ receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound <b>54</b> may be a member of a novel class of candidate drugs for treatment of neuropathic pain

Synthesis and Biological Evaluation of Novel σ₁ Receptor Ligands for Treating Neuropathic Pain: 6‑Hydroxypyridazinones

By use of the 6-hydroxypyridazinone framework, a new series of potent σ₁ receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ₁ receptor affinity (<i>K</i>_i σ₁ = 1.4 nM) and excellent selectivity over not only σ₂ receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)­propoxy)­pyridazin-3­(2<i>H</i>)-one (compound <b>54</b>). Compound <b>54</b> exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound <b>54</b> was evaluated using phenytoin and indicated that the compound was a σ₁ receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound <b>54</b> may be a member of a novel class of candidate drugs for treatment of neuropathic pain

Synthesis and Biological Evaluation of Novel Sigma‑1 Receptor Antagonists Based on Pyrimidine Scaffold As Agents for Treating Neuropathic Pain

The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ₁R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)­propoxy)­pyrimidine (<b>137</b>), which exhibited a high binding affinity to σ₁R receptor (<i>K</i>_i σ₁ = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound <b>137</b> exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound <b>137</b> may constitute a novel class of drugs for the treatment of neuropathic pain