Antianxiety and antidepressant‐like effects of AC‐5216, a novel mitochondrial benzodiazepine receptor ligand

Abstract

1 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. 2 AC-5216 showed high affinity for MBRs prepared from rat whole brain (K i 0.297 nM), rat glioma cells (IC 50 3.04 nM) and human glioma cells (IC 50 2.73 nM), but only negligible affinity for the other main receptors including central benzodiazepine receptors. 3 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 À1 , 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 À1 , p.o.) reduced the immobility time, and this effect was blocked by PK11195. 4 AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitoneinduced sleep in mice, even at doses as high as 1000 mg kg À1 , p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg À1 , AC-5216 (1-100 mg kg À1 , p.o.) produced no distinct change in the rat electroencephalogram. 5 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.

11C-AC-5216: A Novel PET Ligand for Peripheral Benzodiazepine Receptors in the Primate Brain

“…In this study, we selected N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide (AC-5216) ( Fig. 1) (28) as a new candidate for use as a PET ligand for PBR. First, AC-5216 had a higher affinity for PBR prepared from rat brain (inhibition constant [K i ], 0.297 nM) than PK11195 (0.602 nM), a standard ligand for PBR (28).…”

“…1) (28) as a new candidate for use as a PET ligand for PBR. First, AC-5216 had a higher affinity for PBR prepared from rat brain (inhibition constant [K i ], 0.297 nM) than PK11195 (0.602 nM), a standard ligand for PBR (28). Moreover, AC-5216 exhibited negligible affinity for CBR and a large number of other receptors, monoamine transporters, or ion channels.…”

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

“…Novel antidepressants with potentially greater efficacy (NMDA antagonists, glucocorticoid antagonists) not predicted by preclinical tests to be effective. A total of 143 compounds evaluated; 13 launched: 2 ¼ 5-HT 1A , 1 ¼ 5-HT 2A , 1 ¼ CRF modulator, rest BZP (Risbrough et al, 2003;Moret, 2003;Clark et al, 2004;Griebel et al, 1997aGriebel et al, , 1997bGriebel et al, , 2002Kita et al, 2004;McKernan et al, 2000). Preclinical models excellent at predicting in vivo anxiolytic actions and at predicting BZP-like side-effects.…”

Current status and future perspectives: TSPO in steroid neuroendocrinology

“…The drug XBD173 (Emapunil) has been a topic of intense investigation for use as an anxiolytic (Kita et al 2004). Optimistic outcomes were reported using a high dose of XBD173 in an induced model of panic disorder in rats (Rupprecht et al 2009).…”