Nonpeptide vasopressin Vlb receptor antagonists

Guy Griebel1'* and Claudine Serradeil-Le Gal2

' Sanofi-Synthelabo Recherche, Bagneux, France 2 Sanofi-Synthelabo Recherche, Toulouse, France

Abstract: Arginine vasopressin (AVP) is critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF. This observation, taken together with the identification of AVP receptors (e.g. V(b) in limbic structures has led to the idea that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of an orally active nonpeptide V)b receptor antagonist has allowed to verify this hypothesis. Studies in animals have shown that the V|b receptor antagonist, SSR149415, is able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like effects of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. While the latter were active in a wide range of anxiety models, the AVP antagonist showed clear-cut effects only in particularly stressful situations. Moreover, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. heart rate) responses following acute stress exposure in rats, ft is noteworthy that SSR149415 was devoid of central effects not related to emotionality. Altogether, these findings suggest that blockade of central Vlb receptors may represent a new therapeutic strategy for the treatment of depression and some forms of anxiety disorders.

Introduction

The treatment of stress-related disorders remains an active area of research and drug discovery focuses more and more on the involvement of neuroactive peptides in the modulation of emotional behaviors. The rapid advances in the understanding of gene structure and regulation of gene expression, the determination of peptide sequences, the characterization of their receptors, and the successful synthesis of both peptide and nonpeptide receptor ligands have increased the attraction for neuropeptides. Among these, corticotropin-releasing factor (CRF), cholec-ystokinin and tachykinins (substance P, and neurokinin A and B) have been the most extensively studied, but the involvement of other neuroactive peptides such as neurotensin, oxytocin and arginine

"Corresponding author. CNS Research Department, Sanofi-Synthelabo, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France. Tel.: +33 (0) 1 45 36 24 70; Fax: +33 (0) 1 45 36 20 70; E-mail:guy. [email protected]

vasopressin (AVP) has also been considered (Rowe et al, 1995; Griebel, 1999; Aguilera and Rabadan-Diehl, 2000; Bale et al, 2001). Specific and highly potent nonpeptide receptor antagonists have been discovered and developed for AVP (Serradeil-Le Gal, 1998; Thibonnier et al, 2001; Serradeil-Le Gal et al, 2002). One of them has been tested in animal models of anxiety and depression, and as will be shown below, it produced positive effects in these procedures, although its profile differed from those observed with classical anxiolytics and antidepressants (Fig. 1).

Evidence that arginine vasopressin is involved in the regulation of stress response

The nonapeptide AVP, synthesized in the hypothalamic paraventricular (PVN) and supraoptic nuclei, is well known for its role on hydromineral balance, but there is also clear evidence that the peptide plays an important role as a neurotransmitter in the brain (Engelmann et al, 1996) and as a regulator of

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