335 Analgesic Efficacy in Rat Models of Experimental Pain of a New Selective Sigma‐1 Receptor Antagonist

Synthesis and Biological Evaluation of the 1-Arylpyrazole Class of σ1 Receptor Antagonists: Identification of 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862)

“…Its pharmacological activity was shown to correlate closely with drug levels in the brain and with actual occupancy of brain σ 1 Rs . Additionally, 28 potentiated morphine analgesia but not its rewarding effects and showed moderate to high activity in a battery of different pain models, including carrageenan- and CFA-induced inflammatory pain and TNBS-induced chronic visceral pain models …”

“…18 Additionally, 28 potentiated morphine analgesia but not its rewarding effects 34 and showed moderate to high activity in a battery of different pain models, including carrageenan-and CFA-induced inflammatory pain and TNBS-induced chronic visceral pain models. 35 Compound 28 was evaluated in a representative model of neuropathic pain, the partial sciatic nerve ligation model in mice, 36 and was shown to dose-dependently inhibit both mechanical allodynia and thermal hypersensitivity, with ED 50 of 23.4 ± 0.9 and 18.8 ± 1.2 mg/kg, respectively. Interestingly, 28 showed increased potency compared to pregabalin, the gold standard for neuropathic pain treatment in humans (Figure 4).…”

“…3-[2-(2-Bromoethoxy)ethoxy]-1-(3,4-dichlorophenyl)-1Hpyrazole (35). A mixture of 8b (0.23 g, 1 mmol), 1-bromo-2-(2bromoethoxy)ethane (0.51 g, 2 mmol), K 2 CO 3 (0.42 g, 3 mmol), and NaI (0.15 g, 1 mmol) in DMF (12 mL) was stirred at room temperature under a nitrogen atmosphere for 18 h. The inorganic solid was filtered off, and the solvent was evaporated to dryness.…”