The Corpus Callosum

Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand
Br J Pharmacol. 2004 August; 142(7): 1059-1072.

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 (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.
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−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.
4. 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.
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. [emphasis added]
   

Benzodiazepines (BZDs) comprise a family of drugs that exert sedative, anti-anxiety, muscle-relaxing, and anti-seizure properties.  Examples are Ativan, Xanax, Klonopin, Valium, and Librium.  They were developed in response to the toxicity of older sedatives, such as barbiturates.  Barbiturates and similar drugs are dangerous in overdose.  BZDs are not very dangerous in overdoses situations. 

When BZDs were first introduced, they were prescribed, by some practitioners, with little regard for any potential danger.  They were thought to be entirely safe.  Unfortunately, quite a few persons developed physical and/or psychological dependence upon the BZDs.  That is what this is all about: doctors and patients really really want an effective anti-anxiety drug that does not have any potential for abuse or dependence.  If it does not cause any sedation or cognitive impairment, that would be a nice bonus.

Most drugs that enter the drug development pipeline never make it to the pharmacy shelf.  Quite a few never even make it to human trials.  So it is significant that emapunil now has been given to at least some humans.  It doesn't mean that it will even make it to a store near you, but it is a good sign.

The abstract of the Science article follows (full text is not openly available)...

Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects
Science 24 July 2009: Vol. 325. no. 5939, pp. 490 - 493

Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced {gamma}-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

The text includes mention of the human trial:

...Out of 85 subjects, 71 healthy volunteers were randomized to treatment for seven consecutive days with placebo, 10, 30, or 90 mg/day XBD173 or 2 mg/day alprazolam before undergoing a second CCK-4 challenge. 70 subjects completed the study...

...One way ANCOVA revealed a significant difference from placebo in attenuating CCK-4 induced anxiety following both alprazolam and the highest dose of XBD173 (Fig. 3). The number of side effects reported with XBD173 was comparable to the incidence in the placebo group. In contrast, a much higher incidence was reported by the alprazolam treated group, in particular dizziness and somnolence...

...While 57% of the subjects treated with alprazolam complained of withdrawal symptoms such as sleep disturbances or restlessness, these were almost absent in the XBD173 treated groups (table S3B). No serious adverse event occurred during the entire study and there was no need for treatment of withdrawal symptoms. Thus, this placebo controlled parallel group study indicates both anxiolytic properties and clearly less side effects compared to benzodiazepines for XBD173 also in humans...

To clarify: CCK-4 is a molecule that is use in experiments to induce panic attacks.  Alprazolam is the generic name for Xanax.  A few points deserve mention.  For one, 2mg/day of alprazolam is a medium dose.  Most people would not start at 2mg/day.  Thus, the high incidence of adverse effects that was seen in the alprazolam group does not necessarily reflect what would be seen in routine clinical practice.  Second, the absence of signs of dependency in the XBD173 group does not mean that there is no risk of abuse of dependence with XBD173.  The history of medicine is punctuated with high hopes for an absence of such risks, followed by nasty surprises.  (see the Stadol story for an example).  Third, the absence of the adverse effects that we worry about ahead of time, does not imply an overall absence of adverse effects. 

The Science paper reports on a small, short-term, unreplicated study.  There is absolutely no way to know at this point whether there is a meaningful potential for adverse effects in a larger population, over a longer time period.  There also is no way to know if the drug really works. 

If it, or a related molecule, makes it to the marketplace, it will be interesting to see if if works in persons who have a history of BZD tolerance.  Another nonaddicting anxiolytic, buspirone (BuSpar), does not work very well for persons who have already taken BZDs.  Something about exposure to BZDs makes a subsequent trial with BuSpar less likely to work.  But unlike XBD173, BuSpar does not have antipanic effects; it only works for generalized anxiety.  So the BuSpar experience might not indicate anything about what will happen with XBD173.

Note: after I write posts like this one, I always get comments, asking where the drug can be gotten, or when it will be available.  The answers are: you can't get it now, and I have no idea when, or if, it will be available.  I can, however, tell you that it will be too expensive.