Masashi Niwa

Synthesis, structure and quantitative structure-activity relationships of σ receptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines

A set of the title compounds having different substituents (R1, R2) on their phenyl groups was synthesized to find sigma receptor binding affinity. Among the compounds, 2b (R1 = R2 = Cl) has the most potent sigma 1-binding activity, while 2a (R1 = R2 = H, SA4503) was most selective to sigma 1 over sigma 2 receptor. The crystal structures of 2a and 2b were shown, by X-ray crystallography, to be similar except for the one torsional angle of their propylene parts. Quantitative structure-activity relationship study suggested the affinity of the compounds to the sigma 1 receptor was dependent on the electronic feature, Swain-Luptons R or Sz that was derived by molecular orbital method, of R1 and R2.

The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain.

We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED(50) values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. However, the balance of the antinociceptive and sedative effects of SA14867 was better than those of the other two drugs. Orally administered SA14867 (0.1-1mg/kg) significantly improved the decreased pain threshold in a specific alternation of rhythm in an environmental temperature (SART)-stressed model by prophylactic and therapeutic treatment. Improvement in the decreased pain threshold of SA14867-treated animals was attenuated by the opioid receptor antagonist naloxone. Furthermore, orally administered asimadoline (10-100mg/kg) improved the decreased pain threshold in a SART-stressed model, but the doses were close to those known to induce sedative effects. In addition, SA14867 (0.1-1mg/kg) significantly inhibited the arthritis-induced decrease in the pain threshold. Subcutaneously administered morphine (0.1-1mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1-1mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.