Unique spirocyclopiperazinium salt. Part 2: synthesis and structure–activity relationship of dispirocyclopiperazinium salts as analgesics

Three series of spirocyclopiperazinium derivatives 5a–d, 6a–f and 17a–d were synthesized and evaluated for their in vivo analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure–activity relationships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity; (2) it is important to adjust the lipophilic property of compounds to improve analgesic activity.