Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand.
We investigated the ability of N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand, to produce anti-anxiety and antidepressant-like effects in various animal models. AC-5216 showed high affinity for MBRs prepared from rat whole brain (Ki 0.297 nm), rat glioma cells (IC50 3.04 nm) and human glioma cells (IC50 2.73 nm), but only negligible affinity for the other main receptors including central benzodiazepine receptors. AC-5216 produced anti-anxiety effects in the Vogel-type conflict test in rats, and in the light/dark box and social interaction tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg(-1), p.o., respectively. These effects of AC-5216 were antagonized by PK11195, an MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg kg(-1), p.o.) reduced the immobility time, and this effect was blocked by PK11195. AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitone-induced sleep in mice, even at doses as high as 1000 mg kg(-1), p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg(-1), AC-5216 (1-100 mg kg(-1), p.o.) produced no distinct change in the rat electroencephalogram. These results indicate that AC-5216 produces anti-anxiety and antidepressant-like effects that are mediated by MBR, but does not cause the side effects normally associated with conventional benzodiazepines. Hence, AC-5216 shows potential for the treatment of stress-related disorders including anxiety and depression.
Kita
Atsuko
A
Pharmacology & Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd, 33-94 Enoki, Suita 564-0053, Osaka, Japan. atsuko-kita@dainippon-pharm.co.jp
Kohayakawa
Hitoshi
H
Kinoshita
Tomoko
T
Ochi
Yoshiaki
Y
Nakamichi
Keiko
K
Kurumiya
Satoshi
S
Furukawa
Kiyoshi
K
Oka
Makoto
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D045744:Cell Line, Tumor; D003891:Desipramine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004569:Electroencephalography; D006801:Humans; D066298:In Vitro Techniques; D054833:Isoindoles; D008024:Ligands; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D054833:Isoindoles; D008024:Ligands; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D058825:Serotonin 5-HT1 Receptor Agonists; C055267:tandospirone; D003975:Diazepam; D003891:Desipramine