Synthesis and structure-activity relationship of di-(3, 8-diazabicyclo[3.2.1]octane) diquaternary ammonium salts as unique analgesics.
Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.
Liu
Hong
H
School of Pharmaceutical Sciences, Peking University, Beijing, P. R. China.
Cheng
Tie-Ming
TM
Zhang
Hong-Mei
HM
Li
Run-Tao
RT
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D003500:Cyclization; D004195:Disease Models, Animal; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000700:Analgesics; D006574:Heterocyclic Compounds, 2-Ring; C480560:di-(3, 8-diazabicyclo(3.2.1)octane)