Unique spirocyclopiperazinium salt. Part 4: Modification of dispirocyclopiperazinium (DSPZ) salts as analgesics

In order to improve the analgesic activity of lead compound 7a, two series of dispirocyclopiperazinium (DSPZ) salts 9a–h, 10a–e and compounds 14, 15 were synthesized and evaluated for their in vivo analgesic activity both by acetic acid induced writhing test and hot plate test. Compounds 9h, 14, and 15 exhibited better analgesic activities than 7a. Several important structure–activity relationships were revealed from this study: (1) the introduction of aryl group would obviously improve the activity; (2) it was favorable to enhance the analgesic activity and reduce the toxicity to incorporate alkyl group with suitable length in the molecule; (3) carbamate analogues displayed lower toxicity than carboxylic ester analogues; (4) hydroxylation and chlorination of lead compound could increase the analgesic activity in hot plate test.

Compound 9: R = Ph, inhibition of 117.0% in hot plate, dose 0.04 mmol/kg; Z = OH, inhibition of 88.9% in writhing test, inhibition of 91.8% in hot plate, dose 0.04 mmol/kg; Z = Cl, inhibition of 98.4%, dose 0.02 mmol/kg.Figure optionsDownload as PowerPoint slide