Ssr149415

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Fig. 1. Chemical structures of SSR149415 ((2S, 4R)-1-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphe-nyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-4-hydroxy-TV, N-dimethyl-2-pyrrolidine carboxamide, isomer(-)).

pituitary adrenocorticotropin (ACTH) secretion (McCann and Brobeck, 1954; Antoni, 1993; Aguilera, 1994). AVP is critical for adaptation of the hypothalamo-pituitary adrenal (HPA) axis during stress through its ability to potentiate the stimulatory effect of CRF. Both acute and repeated stresses (e.g., restraint, foot shocks) stimulate release of AVP from the median eminence into the pituitary portal circulation and increase expression of the peptide in parvocellular neurons of the PVN (for a recent review, see Aguilera and Rabadan-Diehl, 2000).

Extrahypothalamic AVP-containing neurons have been characterized in the rat, notably in the medial amygdala and the bed nucleus of the stria terminalis, which innervate limbic structures such as the lateral septum and the ventral hippocampus (De Vries and Buijs, 1983; van Leeuwen and Caffe, 1983; Caffe et al, 1987). In these latter structures, AVP was suggested to act as a neurotransmitter, exerting its action by binding to specific G protein-coupled receptors, i.e., Vla and Vlb (Lolait et al, 1995; Vaccari et al, 1998; Young et al, 1999), which are widely distributed in the central nervous system (CNS), including the lateral septum, cortex and hippocampus (Morel et al, 1992; Lolait et al, 1995; Tribollet et al, 1999). The presence of this AVP network suggests a modulatory role of the peptide in limbic functioning. Earlier research has demonstrated that locally applied AVP affects learning and memory, flank marking, hibernation and paternal behavior (De Wied, 1965, 1970;

Koob and Bloom, 1982; Dantzer and Bluthe, 1992; Alescio-Lautier et al, 1993; Engelmann et al, 1996).

The neuroanatomical distribution of AVP and its receptors has also prompted speculation about their functional role in emotional processes leading to studies that investigated the behavioral action of centrally infused peptide V! receptor antagonists in animal models of anxiety. For example, the intra-septal application of the mixed Vla/b receptor antagonist i/(CH2)5Tyr(Et)VAVP was found to produce anxiolytic-like effects in the elevated plus-maze test in rats (Liebsch et al, 1996). Moreover, infusion of an antisense oligodeoxynucleotide to the Via subtype mRNA into the septum of rats has been shown to reduce anxiety in the elevated plus-maze (Landgraf et al, 1995). Furthermore, AVP-deficient rats (i.e. Brattleboro) displayed attenuated conditioning freezing responses (Stoehr et al, 1993). Although there is no direct evidence that AVP or AVP receptor ligands may modulate anxiety or depression in humans, a recent clinical finding showed that AVP release was significantly correlated with anxiety symptoms in healthy volunteers after anxiogenic drug challenge (Abelson et al, 2001). It is reported in this study that volunteers with the highest levels of AVP also showed higher levels of respiratory distress and cognitive anxiety. Abnormalities in AVP levels or receptor activity have been detected in depression (Purba et al, 1996; van Londen et al, 1997; Zhou et al, 2001) and obsessive-compulsive disorder, but have not yet been studied in other anxiety disorders. Moreover, there is evidence suggesting that HPA axis dysregulation in depression may be associated with a shift towards increased vasopressinergic control of the axis (Holsboer and Barden, 1996; Dinan et al, 1999). In this context, it can be hypothesized that AVP receptor antagonists may represent potential agents for the treatment of stress-related disorders.

Behavioral effects of nonpeptide AVP receptor antagonists in animal models of anxiety and depression

Initially, peptide AVP receptor antagonists were developed, but their usefulness was limited because of their peptide nature, poor access to the brain following systemic administration and poor oral bioavailability (Manning and Sawyer, 1993). Recently, several classes of nonpeptide antagonists of AVP receptors (i.e., Vla and V]b) have been discovered by random screening (Paranjape and Thibonnier, 2001; Thibonnier et al, 2001; Serradeil-Le Gal et al, 2002) and have allowed assessment of the potential therapeutic applications of selective blockade of AVP binding sites in stress-related disorders.

Effects of selective blockade of V,b receptors

The first nonpeptide antagonist at the V,b receptor, SSR149415, has been described recently (Serradeil-Le Gal et al, 2002). The compound displays high affinities for both native and recombinant human and rat V]b receptors (human: Kj = 4.2 and 1.5nM, respectively; rat: Kj = 3.7 and 1.3 nM, respectively), 60- and 800-fold selectivity for human and rat V!h as compared to V|a receptor, displayed weak affinity at V2 and OT receptors, and was inactive in more than 90 binding assays for neurotransmitters and peptides. In vivo, SSR149415 did not modify the Via-mediated vascular response following AVP administration and had no effect on diuresis in rats. It is a potent antagonist at the Vib receptor as shown by its ability to inhibit AVP-induced Ca2+ increase in CHO cells expressing the human or rat V|b receptor (K, = 1.26 and 0.73nM, respectively), and AVP-induced ACTH secretion in corticotroph cells in rats. The effects of SSR149415 were investigated in a variety of procedures based on stress-induced changes in behavioral, endocrine, neurochemical, and autonomic nervous system parameters.

Profile in animal models of anxiety

In traditional screening tests for anxiolytics, such as conflict paradigms (e.g., punished drinking procedure

Table 1. Summary of the pharmacological properties of the Vlb receptor antagonist, SSR149415, in rodents. Comparison with diazepam and fluoxetine.

MED or *ED50, mg/kg, po, (ip) or Ssc Tests SSR149415 Diazepam Fluoxetine

Drinking conflict test in rats

(3)

(1)

(>20)

Elevated plus-maze in rats

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