Preclinical anxiolytic profiles of 7189 and 8319, novel non-competitive NMDA antagonists.
Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties (Clineschmidt et al., 1982; Croucher et al., 1982; Bennett and Amrick, 1986). 7189 and 8319, two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety.
Dunn
R W
RW
Hoechst-Roussel Pharmaceuticals, Inc. Somerville, NJ 08876.
Corbett
R
R
Martin
L L
LL
Payack
J F
JF
Laws-Ricker
L
L
Wilmot
C A
CA
Rush
D K
DK
Cornfeldt
M L
ML
Fielding
S
S
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013876:Thiophenes / Q000494:pharmacology*; D014316:Tritium; D015016:Yohimbine
D000814:Aniline Compounds; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D010879:Piperazines; D013876:Thiophenes; D014316:Tritium; C067556:compound 7189; C067557:compound 8319; D015016:Yohimbine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D003975:Diazepam