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Endocrinology Vol. 148, No. 9 4133-4135
Copyright © 2007 by The Endocrine Society

V1b Receptors: New Probes for Therapy

Roberto Arban

Head of Psychopharmacology Department of Biology GlaxoSmithKline Group Psychiatry Centre of Excellence for Drug Discovery Medicines Research Centre 37135 Verona, Italy

Address all correspondence and requests for reprints to: Dr. Roberto Arban, Head of Psychopharmacology, Department of Biology, GlaxoSmithKline Group, Psychiatry Centre of Excellence for Drug Discovery, Medicines Research Centre, Via Fleming, 4, 37135 Verona, Italy. E-mail: Roberto.2.Arban{at}gsk.com.


   Introduction
Top
 Introduction
V1b Receptor Subtype
 d[Leu4,Lys8]VP: A New Selective...
 References
 
The wide range of physiological effects mediated by arginine vasopressin (AVP) raises the possibility that pharmacological agents selectively targeting different components of this peptide system may provide potential novel therapeutic approaches for the treatment of human diseases. AVP receptor subtypes have been proposed as potential targets for the treatment of debilitating disorders such as congestive heart failure, arterial hypertension, dysmenorrhea (V1a receptors), hyponatremia, water retention, ocular hypertension (V2 receptors), and pre-term labor (oxytocin (OT) receptors) (1).

AVP effects are mediated by three 7-transmembrane G protein-coupled receptors that have been defined on the basis of their tissue distribution and pharmacology. The V1a receptor subtype is widely distributed in the vascular wall, central nervous system, liver, kidney, and platelets; V1b receptors are predominantly found in the anterior pituitary. The V2 receptor subtype is distributed almost exclusively in the kidney. Furthermore, AVP binds with appreciable affinity and has agonist activity at the OT receptor, which also belongs to the G protein-coupled receptor superfamily (2).


   V1b Receptor Subtype
Top
 Introduction
 V1b Receptor Subtype
d[Leu4,Lys8]VP: A New Selective...
 References
 
The main role of the V1b receptor is the regulation of ACTH hormone release from the pituitary gland. An emerging body of preclinical and clinical evidence demonstrates that CRH is the physiological mediator of ACTH release under acute stressful conditions, whereas AVP mediates dynamic (pulsatile, circadian) ACTH release under nonstressful conditions (3) and strongly potentiates CRH-induced ACTH release. This situation may be altered in disease states where dysregulation or hyperactivation of the hypothalamic-pituitary-adrenal axis is observed, and the primary control of ACTH release may be shifted from CRH to AVP (4). This suggests that the blockade of V1b receptors could be exploited as a possible therapeutic strategy for the treatment of diseases characterized by excessive cortisol secretion, such as major depression (5) and stress-related disorders (6). Furthermore, V1b receptors are expressed not only in the pituitary gland, but also significantly in brain areas involved in the control of social behavior and emotionality and in the pancreas (7, 8, 9). The role of V1b receptors at these sites is currently under investigation; studies with V1b receptor knockout mice revealed not only changes in hypothalamic-pituitary-adrenal axis regulation (10), as expected, but also profound modification of social behavior (11, 12) and insulin release from the pancreas (13).

Taken together, these data strongly suggest that selective V1b receptor ligands could bring beneficial effects to different patient populations. Identification of such ligands, however, has been a challenging task for the scientific community and only recently have the medicinal chemistry efforts of two independent groups led to the discovery of the peptidergic V1b receptor agonist d[Cha4]AVP (14) and the synthetic small molecule antagonist SSR149415 (15). In particular, SSR149415 has been widely studied in preclinical models, and data obtained to date consistently support the potential therapeutic benefit of blockade of V1b receptors in stress-related disorders (16). SSR149415 has been recently reported to be poorly selective for the V1b receptor and to have significant affinity for the human OT receptor (17); selectivity with respect to the rat OT receptor is reasonable, being ~40-fold in favor of V1b (18). Nevertheless, care must be taken in interpreting results from studies in the rat if high doses of the compound are used. The peptidergic agonist d[Cha4]AVP behaves in an opposite way: It shows good selectivity against human recombinant receptor subtypes (>80-fold), whereas its profile in the rat is far from optimal, in that it shows nonnegligible affinity for the V2 receptor (selectivity ~30-fold in favor of V1b) and thus retains antidiuretic activity in vivo (14). Given the pharmacological tools available at present, there are many questions regarding V1b receptor function that remain to be elucidated despite the use of d[Cha4]AVP and SSR149415. In particular, identification of a compound with an improved selectivity profile may allow the synthesis of a suitable radioligand for autoradiographic and receptor binding studies to shed light on V1b receptor density in different tissues. Furthermore, tissue selective molecules are needed to investigate the effects of AVP on social and stress-related behaviors originating from V1b receptor activation at either the pituitary or at the central level.


   d[Leu4,Lys8]VP: A New Selective V1b Receptor Agonist
Top
 Introduction
 V1b Receptor Subtype
 d[Leu4,Lys8]VP: A New Selective...
References
 
A series of AVP analogs with agonist properties at the V1b receptor has been synthesized recently and characterized against human recombinant AVP and OT receptor subtypes (19). The synthesis of d[Leu4,Lys8]VP as a potential selective ligand at the rat V1b receptor subtype (20) was a subsequent advance, and Pena et al. (21) further characterized d[Leu4,Lys8]VP as superior to previous tools in terms of selectivity. The selectivity of d[Leu4,Lys8]VP is 23-fold with respect to the human recombinant OT receptor and is much higher when assessed against the rat OT ortholog (>150-fold) in receptor binding studies. The compound behaves consistently as a full agonist at the rat V1b receptor in a range of functional bioassays and displays negligible antidiuretic, vasopressor, or oxytocic activity when tested in vivo (21). Like AVP, d[Leu4,Lys8]VP increases insulin release from isolated perfused rat pancreas preparations and dose dependently increases plasma ACTH levels after iv administration. Both effects were fully reversed by administration of SSR149415 (21).

It has thus been suggested that [Leu4,Lys8]VP may provide a novel tool with an improved profile (compared with d[Cha4]AVP and SSR149415) to explore V1b receptor function (21). Caution must be exercised, however, before accepting d[Leu4,Lys8]VP as a significant step forward, and the compound requires further characterization and needs to satisfy a number of criteria.

First, it would be extremely useful to obtain a radiolabeled compound derived from d[Leu4,Lys8]VP with unmodified pharmacological properties. Expression levels in the rat brain, for example, have been explored by immunohistochemistry (7, 8), which provides qualitative data but is not sufficient for quantification of receptor density in discrete areas of tissue. A radiolabeled compound selective for V1b receptor could not only allow the mapping of the V1b receptor subtype by autoradiography, a technique generally more sensitive than immunohistochemistry, but could also be used in receptor binding studies on tissue preparations. Given the peptide nature of d[Leu4,Lys8]VP, it may not be suitable for radiolabeling, though its reduced hydrophobicity compared with other analogs makes d[Leu4,Lys8]VP potentially very promising. Furthermore, the use of a radiolabeled d[Leu4,Lys8]VP derivative for human tissue studies is in any case limited by its lower selectivity with respect to the human OT receptor. Nevertheless, if the approach is successful in the rat, analogs from the same series with improved selectivity for the human V1b receptor may provide a way forward.

A second important advance would be to use d[Leu4,Lys8]VP in vivo not only to study the physiological role of V1b receptors but also to evaluate potential pathological roles. Because such studies are often characterized by chronic modifications and/or prolonged treatment, determination of the metabolic stability of d[Leu4,Lys8]VP in the plasma is of critical importance. In addition, determination of a possible relationship between pharmacological effects and plasma concentrations of d[Leu4,Lys8]VP would be useful, even if active plasma levels are likely to be very low given its potent agonist properties at the target receptor.

Finally, the role of peripheral vs. central V1b receptors in mediating behavioral effects in response to stress needs to be clarified. Both peripheral (22) and central sites (23, 24) have been proposed to be involved in the anxiolytic- or antidepressant-like effects of SSR149415. Stemmelin et al. (24) reported antidepressant-like effects in the rat after direct injection of SSR149415 into brain sites that mediate stress-related behavior; similarly, Salomé et al. (25) demonstrated anxiolytic-like effects after injection of SSR149415 into the rat basolateral amygdala. Similar approaches using d[Leu4,Lys8]VP and the injection of a selective V1b agonist may provide novel information on the role of AVP and V1b receptor functions mediated by specific brain areas. These caveats notwithstanding, d[Leu4,Lys8]VP is a novel promising tool for the study of key aspects of V1b receptor function.

In conclusion, the V1b receptor may provide a novel pharmacological target for the treatment of a range of disease states. The discovery of novel and selective ligands is an essential step to elucidate V1b receptor function and to assess the true therapeutic potential of targeting the AVP peptidergic system.


   Footnotes
 
Disclosure Statement: The author is employed by GlaxoSmithKline.

Abbreviations: AVP, Arginine vasopressin; OT, oxytocin.

Received June 4, 2007.

Accepted for publication June 28, 2007.


   References
Top
 Introduction
 V1b Receptor Subtype
 d[Leu4,Lys8]VP: A New Selective...
 References
 

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