Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327.
DN-2327, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)carbonylmethyl]isoindolin-1-one, produced anxiolytic, taming and anti-convulsive effects when administered orally to several species of animals. DN-2327 produced few of the sedative-hypnotic and muscle-relaxant effects observed with diazepam. The durations of the anxiolytic and anti-convulsive activities of DN-2327 were much longer than those of diazepam. Tolerance to DN-2327 did not develop when it was administered daily for 14 days in an anti-conflict test (Vogel conflict test). DN-2327 showed potent displacement activity against [3H]diazepam binding. The binding affinity of DN-2327 for benzodiazepine receptors was about twenty times that of diazepam. Furthermore, the affinity of DN-2327 for benzodiazepine receptors was not enhanced by the presence of GABA. There is a wide margin between the doses of DN-2327 that cause the anxiolytic effects and its sedative-hypnotic/muscle-relaxant effects. These results suggest that DN-2327 has more marked anxioselective properties compared with the benzodiazepines.
Wada
T
T
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Nakajima
R
R
Kurihara
E
E
Narumi
S
S
Masuoka
Y
Y
Goto
G
G
Saji
Y
Y
Fukuda
N
N
D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002492:Central Nervous System Depressants; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D004285:Dogs; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009125:Muscle Relaxants, Central; D009287:Naphthyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013141:Spiro Compounds / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D009125:Muscle Relaxants, Central; D009287:Naphthyridines; D013141:Spiro Compounds; C060382:pazinaclone; D003975:Diazepam