Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds.
A series of cyclic imides bearing a omega-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT1A receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R*,2S*,-3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (1: tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.
Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
K
K
Ishizumi
A
A
Kojima
F
F
Antoku
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology; D054833:Isoindoles; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
D014151:Anti-Anxiety Agents; D007094:Imides; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; C055267:tandospirone