Involvement of AVPVasopressin Receptors in Psychiatric Disorders

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Anxiety: Anxiety disorders (► Generalized Anxiety Disorder) are associated with feelings of apprehension, tension or uneasiness. The ► amygdala is the region of the brain which is proposed to play a pivotal role in anxiety and fear. This brain structure contains high levels of vasopres-sin receptors and AVP causes excitation of amygdala neurons. Furthermore, animal studies have demonstrated a clear correlation between AVP levels and anxiety behavior (► Anxiety: animal models), and data are emerging to suggest that this correlation may also exist in humans. Unfortunately, the data linking alterations in the AVP system to clinical anxiety disorders are sparse, and more research in this area is warranted. Nevertheless, the pre-clinical data indicate that vasopressin receptors are a suitable target for the development of drugs for the treatment of anxiety-related disorders.

Depression: Major depressive disorder is characterized by depressed mood and lack of pleasure or interest and may include symptoms such as appetite disturbances, sleep abnormalities, concentration difficulties, and suicidal thoughts. Clinical studies have shown that the central AVP system is altered in depressed individuals (Ring 2005). Elevated AVP concentrations in the brain and CSF, and alterations in V1a receptor density in post-mortem analysis of brain tissue from depressed individuals have also been described. Elevated AVP levels in the plasma of depressed patients have also been observed, and the neuroendocrine response to vasopressin agonists is increased in depressed subjects in comparison with healthy volunteers. These data have led to the suggestion that AVP receptor antagonists may prove useful for the treatment of the symptoms of depression (► Antidepressants: Recent Developments).

Schizophrenia: A feature of ► schizophrenia is a deficit in the ability to filter out unnecessary information. These deficits are exhibited in measures such as ► pre-pulse inhibition (PPI) in which a weaker prestimulus inhibits the reaction of an organism to a subsequent strong startling stimulus. Deficits in PPI have been described in V1b-receptor knock-out mice, indicating that loss of vasopressin receptor function can cause sensory-gating abnormalities. Abnormalities in levels of plasma, CSF, and brain AVP in schizophrenic patients have been described, but not consistently across all studies. Given that AVP has been implicated in regulation of social cognitive behaviors and dysfunction of these behaviors are a core symptom of schizophrenia, it is possible that abnormalities in the central AVP system may underlie these symptoms. However, the data supporting this hypothesis should be considered as being preliminary.

Autism: Individuals diagnosed with autistic disorder (► Autism Spectrum Disorders and Mental Retardation) generally appear to be uninterested in social contact, exhibit impaired communication, and display patterns of repetitive behavior. Autistic disorder is believed to result from a complex interaction between several genetic and environmental factors, although the exact mechanisms involved are poorly understood. Considering that a role for AVP in modulation of social behavior has been established, it is plausible to suggest that alterations in the AVP system may underlie at least some of the behavioral abnormalities that are associated with autism (Frank and Landgraff 2008). Genetic analysis of the regulatory region upstream of the V1a receptor gene has identified a polymorphic microsatellite which is associated with autism. However, little is known about the functional impact of these genetic variations on V1a gene expression, and whether they contribute to the behavioral changes associated with autism is open to debate. Further studies are therefore required to establish whether alterations in the AVP system contribute to the symptoms of autism.

Vasopressin Receptor Antagonists in Psychiatric Drug Development

Vasopressin V1a and V1b receptor antagonists are widely recognized to represent a novel approach for the treatment of depression and anxiety. The identification and development of high-affinity, nonpeptidic ligands with the desired drug-like properties for oral bioavailability (and CNS penetration), however, is proving challenging.

V1a Antagonists: A number of pharmaceutical companies have developed potent-selective V1a antagonists for peripheral indications such as cardiovascular/circulatory indications and dysmenorrhoea (pelvic pain associated with menstruation). Few V1a antagonists, however, have been identified with good brain penetration, a prerequisite for psychiatric drug development given the localization of the V1a receptor. Azevan Pharmaceuticals describe two CNS penetrant compounds: SRX-246 (4-(bipiperidin-10-yl)-4-oxo-2(R)-[2-oxo-3(S)-[2-oxo-4 (S)-phenyloxazolidin-3-yl]-4(R)-(2-phenylvinyl)azetidin-1-yl]-N-[1(R)-phenylethyl]butyramide) and SRX-251 (4-(bipiperidin-10-yl)-N-methyl-oxo-2(R)-[2-oxo-3(S)-[2-oxo-4(S)-phenyloxazolidin-3-yl]-4(R)-(2-phenylvinyl) azetidin-1-yl] -N-[3-(trifluoromethyl)benzyl]butyramide), achieving brain levels of compound ~100 times in vitro receptor affinities following oral dosing. SRX-251 is being evaluated in the clinic for the treatment of pain associated with primary dysmenorrhoea and preclinically for the management of agitation and violence. SRX-251 reduces aggression in a hamster model of offensive aggression with no effect on olfactory communication, motor activity, or sexual motivation (Ferris 2006). SRX-246 is currently in preclinical development for the treatment of anxiety/depression. Johnson and Johnson have described JNJ-17308616 (N-(2-(dimethylamino)ethyl)-1-(4-(2-fluorobenzamido)benzoyl)-1,2,3,5-tetrahydrospiro [benzo[b]azepine-4,10-cyclopent[2]ene] -30-carboxamide), a potent and selective V1a antagonist both in vitro and in vivo. The anxiolytic activity of JNJ-17308616 has been demonstrated by a number of groups in a variety of

Arginine Vasopressin Mice
Arginine-Vasopressin. Fig. 2. V1a Antagonists in psychiatric drug development.

animal models of anxiety behavior (► Anxiety: animal models), including the rat-elevated plus-maze, rat-elevated zero-maze, rat-conditioned lick suppression, rat- and guinea pig-pup separation-induced ultrasonic vocalization and mouse marble burying. JNJ-17308616 was also shown to reduce isolation-induced aggression in mice. JNJ-17308616 neither impaired social recognition, induced sedation nor reduced locomotor activity (Fig. 2).

V1b Antagonists: Given the localization of the V1b receptor in the anterior pituitary, and the role of this receptor in driving the neuroendocrine stress response, CNS penetration may not be a requirement for a V1b antagonist aimed at treating psychiatric disorders. To date, only two pharmaceutical companies, Sanofi-Aventis and Abbott Laboratories, have progressed selective V1b antagonists into clinical development. Nelivaptan (SSR-149415) was being evaluated by Sanofi-Aventis in clinical trials for the treatment of anxiety and depression, but was discontinued for both indications in 2008. Preclinical data reported by Sanofi-Aventis have shown that nelivaptan (SSR-149415) (Fig. 3) reduces CRF- and AVP-induced increases in plasma ACTH in male rats (Frank and Landgraff 2008). Nevilaptan (SSR-149415) is reported to strongly reverse stress-induced behavior as measured in the rat-elevated plus-maze, mouse defense test battery, rat- and guinea pig-pup separation-induced ultrasonic vocalization models (► Anxiety: animal models), supporting the rationale for a V1b antagonist in the treatment of stress-induced anxiety. Anti-depressant-like activity was

Arginine-Vasopressin. Fig. 3. V1b Antagonists in psychiatric drug development.

also demonstrated in the forced swim test model of depression (► Depression: Animal Models) and in the differential reinforcement of low rate 72s (DRL-72s) model (► Operant Behavior in Animals). Abbott Laboratories are investigating a series of selective V1b antagonists in the clinic for the potential treatment of depression and anxiety. In preclinical studies, two compounds ABT-436 and ABT-558 (structures not reported) were shown to inhibit vasopressin- and stress-induced increases of stress hormones in mice, a preclinical model of the HPA axis dysregulation implicated in depression and anxiety. ABT-436 and ABT-558 were shown by Abbott to have comparable antidepressant and anxiolytic effect to nelivaptan (SSR-149415) in preclinical behavioral models (Fig. 2).

The identification and development of vasopressin antagonists targeting CNS receptor subtypes represents a promising new therapeutic class for the treatment of anxiety and depression. As such, selective V1a and V1b and mixed V1a/V1b antagonist programs remain a focus for many pharmaceuticals with increasing numbers of novel chemical series appearing in the patent literature.

Cross-References

► Excitatory postsynaptic currents

► G-protein-coupled receptor

► Glucocorticoid

References

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Symp 268:190-200 Ferris CF (2006) Orally active vasopressin V1a receptor antagonist, SRX 251, selectively blocks aggressive behaviour. Pharmacol Biochem Behav 83:169-174

Frank E, Landgraff R (2008) The vasopressin system - From antidiuresis to psychopathology. Eur J Pharmacol 583:226-242 Ingram CD, Ciobanu R, Coculescu IL, Tanasescu R, Coculescu M, Mihai R (1998) Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus. Prog Brain Res 119:351-364 Pittman QJ, Chen X, Mouihate A, Hirasawa M, Martin S (1998) Arginine vasopressin, fever and temperature regulation. Prog Brain Res 119:383-392

Raggenbass M (2008) Review of cellular electrophysiological actions of vasopressin. Eur J Pharmacol 583:243-254 Ring RH (2005) The central vasopressinergic system: examining the opportunities for psychiatric drug development. Curr Pharm Des 11:205-225

Toba K, Ohta M, Kimura T, Nagano K, Ito S, Ouchi Y (1998) Role of brain vasopressin in regulation of blood pressure. Prog Brain Res 119:337-349

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