Searching for Mechanisms of Analgesic Activity in the Group of 1H-Pyrrolo[3,4-c]pyridine-1,3(2H)-dione Derivatives—In Vitro and In Vivo Studies

The present study was to evaluate the analgesic activity of two newly synthesized 1<i>H</i>-pyrrolo[3,4-<i>c</i>]pyridine-1,3(2<i>H</i>)-dione derivatives, designated <b>DSZ-13</b> and <b>DSZ-19</b>. To achieve the desired result, the in vitro XTT cell proliferation assay, serotonin 5-HT_1A receptor affinity and COX-1 and COX-2 enzyme inhibition potential of the compounds were conducted by real-time qPCR. Non-compartmental analysis was used to estimate the pharmacokinetic parameters of the compounds in serum and brain tissue. The analgesic activity was evaluated using various in vivo pain models, encompassing acute pain (hot plate test), tonic pain (formalin test), neurogenic pain (capsaicin test), carrageenan-induced acute inflammation, and neuropathic pain models. Both compounds showed moderate affinity for serotonin 5-HT_1A receptors, a lack of cytotoxic activity, desirable pharmacokinetic parameters and slightly reduced mRNA expression for COX-1 and COX-2. Only the <b>DSZ-19</b> revealed central/supraspinal analgesic activity and did not affect movement. Both compounds attenuated tonic and neurogenic pain, in the formalin and capsaicin tests, respectively. In addition, the involvement of the 5-HT_1A receptors in the formalin test was confirmed. Both compounds also showed antiallodynic activity in the oxaliplatin- and streptozotocin-induced neuropathy models. Slightly weaker than indomethacin, <b>DSZ-13</b> and <b>DSZ-19</b> attenuated carrageenan-induced inflammation (edema) and hyperalgesia in rat models.