The process of proving that a promising compound can have a viable therapeutic application is more often than not a case of having the right tools for the task.

Take, for example, stress-related disorders. It is widely accepted that arginine vasopressin (AVP) is involved in various behavioural processes. It has also been shown that chronic immobilization stress increases levels of vasopressin V1b receptor in the brain, and that this receptor is involved mainly in modulating the effect of AVP on corticotropin secretion — a crucial component in the response to stress or emotional situations. But, without the existence of a V1b receptor antagonist, the role of the V1b receptor in controlling emotional processes could not be proved.

Now, two papers from the same laboratory report the characterization of SSR149415, a selective, non-peptide, orally active V1b receptor antagonist, which they hope will be an innovative approach for the treatment of stress-related disorders.

In the first paper, published in The Journal of Pharmacology and Experimental Therapeutics, Serradeil-Le Gal and colleagues showed that SSR149415 has high affinities for both native and recombinant human and rat V1b receptors, has a much lower affinity for other vasopressin receptors, and was inactive in >90 binding assays for neurotransmitters and peptides. They also showed that SSR149415 is a potent antagonist, as it inhibited both AVP-induced Ca2+ increase in Chinese hamster ovary cells that expressed the human or rat V1b receptor, and AVP-induced corticotropin secretion in rats.

The second report, published in the Proceedings of the National Academy of Sciences, looked at the effects of SSR149415 in animal models of anxiety and depression. When Griebel and colleagues tested SSR149415 in classical models of anxiety (such as the light/dark, the elevated plus-maze and the punished drinking tests), it produced anxiolytic (reduced anxiety) effects, although the magnitude of these effects were less than that of the benzodiazepine diazepam. However, the authors found that SSR149415 produced a clear anxiolytic effect in models of traumatic stress exposure (the social defeat paradigm and the defence test battery).

When Griebel and colleagues looked at classical models for depression (forced swimming and chronic mild stress tests), they found that SSR149415 showed a dose-dependent antidepressant-like activity, which was comparable to those that were observed with the antidepressants fluoxetine and imipramine.

So, it seems that V1b receptor antagonists could provide a new strategy for the treatment of some depressive and anxiety disorders. And although the site of action of SSR149415 is uncertain, it should serve as a useful tool for investigating the functional importance of the brain AVP in emotional processes.