Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents

https://doi.org/10.1016/S0079-6123(08)00437-8Get rights and content

Abstract

Oxytocin (OT) and vasopressin (AVP) mediate their biological actions by acting on four known receptors: The OT (uterine) and the AVP V1a (vasopressor), V1b (pituitary), V2 (renal) receptors and a fifth putative AVP V1c? (vasodilating) receptor. This presentation will summarize some highlights of the recent progress, in the design and synthesis of selective peptide agonists, antagonists, radioiodinated ligands, fluorescent ligands and bivalent ligands for these receptors. Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands. The pharmacological properties of promising new selective OT antagonists and V1b agonists are also presented. This review should serve as a useful guide for the selection of the most appropriate ligand for a given study. The current status of non-peptide OT and AVP antagonists and agonists is also summarized. The relative merits of peptide and non-peptide AVP and OT agonists and antagonists as: (1) research tools and (2) therapeutic agents will be evaluated. Many of the receptor selective peptide agonists and antagonists from this and other laboratories are far more widely used as pharmacological tools for studies on the peripheral and central effects of OT and AVP than their non-peptide counterparts. In addition to OT and to a lesser extent AVP (pitressin), a number of OT and AVP analogues; such as carbetocin (OT agonist) dDAVP (desmopressin, V2 agonist), terlipressin (V1a agonist), felypressin (V1a agonist) and atosiban (Tractocile OT antagonist) are also in clinical use. Despite much early promise, no non-peptide V1a or OT antagonists are currently in clinical trials. While a number of orally active non-peptide V2 antagonists (Vaptans); notably, Tolvaptan, Lixivaptan and Satavaptan, are currently in Phase III clinical trials; to date, only the mixed V2/V1a, antagonist Conivaptan (Vaprisol), has been approved by the US FDA for clinical use (by i.v. administration), for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Promising new non-peptide V1b and OT antagonists, as well as non-peptide V2 and OT agonists are now in pre-clinical development.

Introduction

The past 12 years, have witnessed an extraordinary resurgence of interest in all aspects of neurohypophysial peptide research, including the emergence of a wide variety of more selective agonists and antagonists (both peptide and non-peptide) of the vasopressin (AVP) and oxytocin (OT) receptors. In addition to the numerous publications which have appeared in peer-reviewed journals in the past 12 years, 6 World Congresses on the Neurohypophysial Hormones (WCNH) were held in: (1) Nasu, Japan in 1995 (Saito et al., 1995b), (2) Montreal, Quebec in 1997 (Zingg et al., 1998), (3) Edinburgh, Scotland in 1999 (Douglas et al., 2000), (4) Bordeaux, France in 2001 (Poulain et al., 2002), (5) Kyoto, Japan in 2003 (Kawata and Leng, 2004) and (6) Steamboat Springs, Colorado in 2005. Proceedings from the 2005 WCNH were published in different issues of the Journal of the American Physiological Society. The 7th WCNH was held in Regensburg, Germany in September 2007: (Landgraf and Neumann, 2008). Numerous studies exploring the central and peripheral effects of OT and AVP, using peptides from these laboratories were reported at all seven WCNH's. In addition, during this period, numerous studies, reported in peer reviewed journals have utilized OT and AVP peptide agonists and antagonists, obtained either from the Manning laboratory or from commercial sources (see Pena et al., 2007a for some examples).

OT and AVP receptors belong to a G-protein coupled receptor family characterized by seven putative transmembrane helices. For recent reviews on AVP and OT receptors see Jard, 1998; Barberis et al., 1999; Gimpl and Fahrenholz, 2001; Holmes et al., 2003, Holmes et al., 2004. OT receptors (OTRs) are expressed in the uterus, the mammary gland, the ovary, the brain, the kidney, the heart, bone and in endothelial cells (Gimpl and Fahrenholz, 2001). In the uterus, OTRs mediate the uterine contracting (oxytocic) effect of OT (Gimpl and Fahrenholz, 2001). The central effects of OT continue to be the focus of intense investigative scrutiny in animals (Insel and Young, 2001; Bosch et al., 2005; Huber et al., 2005; Ma et al., 2005; Parker et al., 2005; Ring et al., 2006) and in humans (Hollander, 2007, Hollander et al., 2003; Kirsch et al., 2005), as a possible therapeutic agent for the treatment of autism and other anxiety disorders.

AVP mediates its actions through three known receptors: V1a, V1b and V2 and a putative vasodilating V1c? receptor. V1a receptors are expressed in the liver, vascular smooth muscle cells, brain and in many other tissues (Jard, 1998; Barberis et al., 1999; Holmes et al., 2003, Holmes et al., 2004; Treschan and Peters, 2006). In the vasculature, V1a receptors mediate the pressor actions of AVP by a phospholipase C mediated pathway. In brain, V1a receptors mediate the anxiety (Ma et al., 2005; Ring, 2005) and aggression (Ferris et al., 2006) producing responses to AVP. V1b receptors, present in the anterior pituitary, mediate the ACTH releasing effects of AVP, also by a phospholipase C mediating pathway (Jard, 1998). In a number of publications (Robert et al., 2005), the V1b receptor is also referred to as the V3 receptor. According to the IUPHAR nomenclature, V3 is no longer acceptable. Evidence for the presence of V1b receptors in extra-pituitary tissues such as brain, the kidney and the adrenal medulla has also been reported (Saito et al., 1995a, Saito et al., 1995b). Recently the V1b receptor has been shown to mediate anxiety and stress in rats and in humans (Landgraf, 2006). V2 receptors, present in the collecting duct of the kidney, mediate the antidiuretic action of AVP by an adenylate cyclase mediated pathway (Jard, 1998; Barberis et al., 1999; Holmes et al., 2003, Holmes et al., 2004). The pain response to AVP in the rat appears to be modulated by V2 receptors (Yang et al., 2006). Besides its antidiuretic and vasoconstrictor properties, AVP can also cause vasodilation (Liard, 1989; Hirsch et al., 1989; Walker et al., 1989; Tagawa et al., 1995; Van Lieburg et al., 1995). The receptor subtype that mediates the vasodilating actions of AVP has to date not been characterized. Studies aimed at doing so have been hampered by the lack of specific vasodilating AVP agonists or antagonists. We recently reported the serendipitous discovery of highly selective AVP hypotensive peptides (Chan et al., 1998; Manning et al., 1999, Manning et al., 2007; Stoev et al., 2006).

Besides their value as pharmacological tools and radioligands, OT and AVP antagonists are of potential clinical value. Antagonists of OT are of potential therapeutic value for the prevention of premature labour (Tsatsaris et al., 2004; Manning et al., 2005; Reinheimer et al., 2005; Stymiest et al., 2005; Akerlund, 2006; Flouret et al., 2006; Tan et al., 2006). Atosiban (d[d-Tyr(Et)2,Thr4,Orn8]vasotocin), a peptide OT antagonist (Melin et al., 1986; Romero et al., 2000; Valenzuela et al., 2000) is the only tocolytic, approved (in Europe) under the tradename Tractocile in, 2001, for the prevention of premature birth (Akerlund, 2006). Non-peptide AVP V2 antagonists have potential therapeutic value for the treatment of the hyponatremia caused by the syndrome of inappropriate secretion of the antidiuretic hormone (SIADH) (Serradeil-Le Gal et al., 2002b; Hays, 2006; Palm et al., 2006; Schrier et al., 2006; Streefkerk and van Zwieten, 2006; Verbalis, 2006; Cawley, 2007; Chen et al., 2007; Gines, 2007; Munger, 2007; Parashar et al., 2007). The non-selective non-peptide AVP V2/V1a antagonist, Conivaptan (YM-087) (Tahara et al., 1998, Tahara et al., 1997) under the tradename “Vaprisol” was approved for the treatment, by i.v. only, of euvolemic hyponatremia by the FDA in 2005 (Ghali et al., 2006; Verbalis, 2006). Earlier this year, it received FDA approval for the treatment of hypervolemic hyponatremia. Non-peptide V2 and V2/V1a antagonists may also have value for the treatment of heart failure (Abraham et al., 2006; Schwarz and Sanghi, 2006). They also have potential as pharmacochaperones for the treatment of X-linked nephrogenic diabetes insipidus (NDI) (Bernier et al., 2006; Robben et al., 2007). Three selective non-peptide V2 antagonists are currently in clinical trial (Verbalis, 2006): Tolvaptan (OPC 41061) (Yamamura et al., 1998), Satavaptan (SR 121 463) (Serradeil-Le Gal et al., 1996) and Lixivaptan (VPA-985) (Albright et al., 1998; Schrier et al., 2006; Soupart et al., 2006). However none has yet been approved by the FDA. Antagonists of the vascular responses (V1a receptor) to AVP may have clinical potential for the treatment of those patients with hypertension or congestive heart failure (CHF) with concomitant elevated plasma AVP levels (Thibonnier et al., 2001). They may also be of value as “serenics” in the management of anger (Ferris et al., 2006). However, with the exception of the V1a antagonist SRX-251 (Ferris et al., 2006; Guillon et al., 2007a, Guillon et al., 2007b), none are currently in clinical trial. Non-peptide AVP V1b antagonists could be of value as diagnostic agents and as therapeutic agents for the treatment of ACTH secreting tumours (Serradeil-Le Gal et al., 2002a, Serradeil-Le Gal et al., 2002b, Serradeil-Le Gal et al., 2007) and for treating anxiety and stress (Griebel et al., 2002; Craighead and MacSweeney, 2008).

Section snippets

Scope of the this presentation

This review will focus on documenting the pharmacological properties of the most widely used OT and AVP peptide agonists and antagonists, while also providing data on more promising newer peptides. Space limitations preclude the inclusion of more than the sketchiest details on how these peptides were designed. The original publications and reviews such as (Manning et al., 1981; Hruby and Smith, 1987; Lebl, 1988; Manning and Sawyer, 1989, Manning and Sawyer, 1993) should be consulted for more

Peptide synthesis

All the OT and AVP agonists, antagonists, radiolabelled and fluorescent ligands from our laboratories were synthesized using the Merrifield solid-phase method (Merrifield, 1963; Stewart and Young, 1984). The procedures used are described in the original publications cited here. For other references see Manning (2008).

Bioassays

Peptides from our laboratories were assayed for agonistic and antagonistic activities in in vitro and in vivo rat oxytocic assays in the rat vasopressor assay and in the rat antidiuretic assay. For agonists, the four-point assay design (Holton, 1948) was used and for antagonists, Schild's pA2 method (Schild, 1947) was employed. The pA2 is the negative logarithm of the molar concentration of the antagonist that will reduce the response to 2x units of the agonist to equal the response to 1x unit

Receptor binding and functional assays

Membranes and/or cell lines which express the rat and human AVP V1a, V1b and V2 receptors (Birnbaumer et al., 1992; Lolait et al., 1992; Morel et al., 1992; De Keyzer et al., 1994; Sugimoto et al., 1994; Thibonnier et al., 1994) and the human OT receptor (Kimura et al., 1992) were used for binding and functional assays: inositol phosphate accumulation (Bone et al., 1984) for V1a, V1b and OT receptors and cyclic AMP accumulation (Salomon et al., 1974) for V2 receptors, as previously described (

Potent and/or selective oxytocin and vasopressin agonists

OT and AVP have very similar structures and differ only at position 3 and 8 (Table 1, Table 2, Table 3). Their structures are as follows:

Because of the similarity of their structures, they exhibit a spectrum of overlapping pharmacological properties in rat bioassays (Table 1, Table 2). Table 1 provides the pharmacological properties of some widely used analogues of OT which exhibit greater potency and/or selectivity than OT in the oxytocic, antidiuretic and/or vasopressor rat bioassays. Thus

Selective agonists for human and rat V1b receptors

Following the historic original synthesis of OT and AVP in the du Vigneaud laboratory (du Vigneaud et al., 1954a, du Vigneaud et al., 1954b), selective agonists for the AVP V1a and V2 receptors were uncovered relatively easily in the mid to late sixties, by classical structure activity studies (for reviews see Berde and Boissonnas, 1968; Hruby and Smith, 1987; Jost et al., 1988; Manning and Sawyer, 1989, Manning and Sawyer, 1993) (Table 4, Table 5, Table 6, Table 7). For a variety of reasons,

Non-selective rat and human V1b/V1a antagonists

To date, there are no selective peptide V1b antagonists. However, as shown in Table 11, Table 12, a number of cyclic and linear V1a antagonists have been shown to exhibit VP V1b antagonism for rat and/or human receptors in vitro and in vivo. A recent study by Ma et al. (2005) reported that the cyclic V1b/V1a antagonist dP[Tyr(Me)2, Arg–NH29]AVP (Manning et al., 1992b) blocked the ACTH releasing effects of AVP in vivo in the rat. This peptide was also recently reported (Serradeil-Le Gal et al.,

Cyclic and linear V2/V1a antagonists for rat VP receptors

Table 13 lists non-selective and selective cyclic and linear AVP V2/V1a antagonists in the rat: Peptides 1–5 are cyclic and Peptides 6–10 are linear (Manning and Sawyer, 1989, Manning and Sawyer, 1993). Peptides 3–5 are selective for V2 versus V1a receptors. Thus d(CH2)5[d-Ile4, Ile4]AVP, with an ED Ratio of 39, desGly–NH2, d(CH2)5[d-Ile2, Ile4]AVP, with an ED ratio of 400 and d(CH2)5[d-Ile2, Ile4, Ala–NH29]AVP, with an ED ratio of 83 have all been utilized in a wide variety of studies, as

V2 Antagonist with high affinity for human V2 receptor

The development of peptide AVP V2/V1a antagonists for use as aquaretics in humans was abandoned at Smith Kline Beecham following the discovery that the lead V2/V1a candidate, desGly, d(CH2)5[d-Tyr(Et)2,Val4]AVP (Manning et al., 1984) (peptide 2, Table 13) was an agonist in humans (Ruffolo et al., 1991) (Table 14). With the emergence of non-peptide V2 antagonists (see below), no further attempts were made to find a peptide V2 antagonist which would be an effective V2 antagonist in humans. We now

Development of highly selective OT antagonists in the rat and in humans

Since this subject was last reviewed (Manning and Sawyer, 1993), we have designed and synthesized a number of highly selective OT antagonists (Manning et al., 1995a; Chan et al., 1996; Manning et al., 2005, Manning et al., 2001). A number of these are slowly being adopted as substitutes for one or our original OT antagonists, d(CH2)5[Tyr(Me)2]OVT (peptide 2, Table 15). In the rat, this OTA is actually 5 times more potent as a V1a antagonist than as an OT antagonist (Bankowski et al., 1980).

OT Antagonists with high affinities and selectivities for the human OT receptor

Table 16 contains a number of new OT antagonists which have strikingly higher affinities for the human receptor than the peptide OT antagonist, Atosiban (Manning et al., 2005). To date, Atosiban is the only OT antagonist, peptide or non-peptide which has been approved (in Europe) for clinical use as a tocolytic or the prevention of premature labour (Romero et al., 2000; Valenzuela et al., 2000; Vatish and Thornton, 2002; Tsatsaris et al., 2004).

Peptides 1–4 (Table 16), the four most promising

Radiolabelled ligands for rat and/or human vasopressin and oxytocin receptors

Tritiated and radioiodinated ligands for AVP and OT receptors (Table 17) have found widespread use in receptor localization and identification studies (for references see Manning et al., 1995b). Until the discovery of radioiodinated ligands, these studies relied solely on tritiated ligands. While tritiated OT is specific for rat and human OT receptors, tritiated AVP and LVP lack specificity for a single receptor subtype. The tritiation of the selective OT receptor agonist, [Thr4,Gly7]OT (Elands

High affinity fluorescent agonists and antagonists for human OT and AVP receptors

Previous studies have shown the value of fluorescent AVP analogues for studies on rat and human AVP receptors (Buku et al., 1989, Buku et al., 1988; Eggena and Buku, 1989; Buku and Gazis, 1990; Lutz et al., 1990; Guillon et al., 1992; Howl et al., 1993; Thibonnier et al., 1993). Table 18, Table 19 list some new fluorescent agonists and antagonists for the human OT and AVP receptors. The fluorescent OT agonists in Table 18 exhibit very high affinities and selectivities for the human OT receptor (

Bivalent ligands for human and rat OT and V1a receptors

As part of a study on chimeric peptides, Wheatley and colleagues reported the first bivalent ligands of a linear V2/V1a antagonist for the rat V1a and V2 receptors (Howl et al., 1997) (Table 20). We recently reported the syntheses and some preliminary pharmacological properties of bivalent ligands for the hOTR, V1a and V1b receptors (Chini et al., 2007; Chini and Manning, 2007). Suberic acid, (HOOC–(CH2)6–COOH) utilized as reported by Gera et al. (1996), served as the spacer joining Orn or Lys

Non-peptide vasopressin and oxytocin antagonists and agonists

Since the discovery of the first non-peptide V1a antagonist by Otsuka (Yamamura et al., 1991), at least 10 other pharmaceutical companies have published non-peptide V1a, V1b, V2, V2/V1a and OT antagonists. Also, more recently, at least three companies have reported non-peptide agonists for the V2 receptor and for the OT receptor. To date, there are no reports on non-peptide V1a or V1b agonists. The current status of the development and clinical trials on non-peptide antagonists and agonists is

Non-peptide V1a receptor antagonists

Following the report in 1991 by the Otsuka company of the first non-peptide V1a antagonist OPC-21268 (Yamamura et al., 1991) a number of other companies, most notably Sanofi-Synthelabo, Yamanouchi, and Fujisawa (the two latter now combined as Astellas) have developed other non-peptide V1a antagonists (Table 21). Among the most promising are SR49059 (Relcovaptan), developed by Sanofi in 1993 (Serradeil-Le Gal et al., 1993), YM218, developed by Yamanouchi in 2005 (Tahara et al., 2005), and

Non-peptide V2 antagonists (Vaptans, Table 21)

The report by Otsuka in 1992 of the first non-peptide V2 antagonist OPC-31260 (Mozavaptan) (Yamamura et al., 1992), elicited much interest in the development of other non-peptide V2 antagonists for the treatment of hyponatremia at six other pharmaceutical companies. To date, these studies have uncovered a variety of orally active non-peptide V2 antagonists shown to be effective as aquaretics in animals and in humans. As a class, these have been termed Vaptans. (For reviews see: Thibonnier et

Non-peptide V2/V1a antagonists

The dual non-peptide V2/V1a antagonist YM-087 (Conivaptan), developed at Yamanouchi (Tahara et al., 1998, Tahara et al., 1997) and marketed under the name Vaprisol by Astellas Pharma is the only Vaptan approved by the US FDA for i.v. use in the treatment of hyponatremia (Verbalis, 2006; Walter, 2007) (Table 21). This dual non-peptide V2/V1a antagonist thus holds the distinction of being the first non-peptide AVP antagonist approved for clinical use. It is somewhat ironic, that in view of all

Non-peptide V1b antagonists

To date, only two companies, Sanofi, and Organon have reported success in this area (Table 21). The first non-peptide V1b antagonist SSR-149415 was reported in 2002 (Serradeil-Le Gal et al., 2002a, Serradeil-Le Gal et al., 2002b). SSR-149415 is orally active and was reported to possess high and selective affinity for rat and human V1b receptors in vitro and in vivo (Serradeil-Le Gal et al., 2002a, Serradeil-Le Gal et al., 2005, Serradeil-Le Gal et al., 2002b). This non-peptide V1b antagonist

Non-peptide oxytocin antagonists

The emergence of orally active non-peptide OT antagonists at the Merck laboratories in the early nineties (Evans et al., 1992) appeared to fill a therapeutic void for an effective orally active tocolytic for the treatment and prevention of premature labour (Table 22). However, due to suboptimal pharmacokinetics and oral bioavailability, clinical trials with what appeared to be a promising OT antagonist (L-368,899), (Pettibone et al., 1993; Williams et al., 1995) were discontinued (Freidinger

Non-peptide vasopressin agonists

To date, three companies have been active in this area Otsuka, Ferring and Wyeth Ayerst (Table 23). The only non-peptide AVP agonists reported to date are selective for the AVP V2 receptor. To date, no non-peptide agonists have been reported for the AVP V1a or V1b receptors. In 2000, Otsuka reported the first non-peptide V2 agonist OPC-51803 (Nakamura et al., 2000; Kondo, 2002). This non-peptide V2 agonist has been reported to have advantages, in terms of receptor selectivity and oral

Non-peptide oxytocin agonists

This area has seen very little activity over the years (Table 24). However the recent surge in studies showing that OT may be of therapeutic value for the treatment of a wide variety of neuropsychiatric diseases, including, autism, anxiety related disorders and schizophrenia (Insel and Young, 2001; Hollander, 2007, Hollander et al., 2003; Neumann et al., 2003, Neumann et al., 2006; Bosch et al., 2006, Bosch et al., 2005; Ebner et al., 2005; Kirsch et al., 2005; Kosfeld et al., 2005; Hammock and

Peptides as research tools

By virtue of their water solubility, peptides are clearly superior to non-peptides as research tools. Literally, many hundreds of studies have been carried out with peptide agonists, antagonists, radiolabelled and fluorescent ligands for the AVP and OT receptors (see Sawyer et al., 1988; Sawyer and Manning, 1988; Manning and Sawyer, 1989, Manning and Sawyer, 1993). The following are examples of highly significant studies carried out with AVP and OT peptide agonists and antagonists during the

Species differences and lack of specificity

Species differences (Howl et al., 1991; Ruffolo et al., 1991; Pettibone et al., 1992; Thibonnier et al., 1997; Tahara et al., 1999; Andres et al., 2004; Guillon et al., 2004; Chini and Manning, 2007; Chini et al., 2008) and lack of specificity for a given receptor (Manning and Sawyer, 1989, Manning and Sawyer, 1993; Chan et al., 2000; Chini et al., 2008) continue to be a concern in this field. We have attempted to address these problems in this review, by presenting the pharmacological

Peptides as therapeutic agents

OT, Carbetocin, [1-deamino-1-monocarba-2-O-methyltyrosine]oxytocin (Su et al., 2007), AVP (Pitressin), dDAVP (Desmopressin) (Minirin) (Makaryus and McFarlane, 2006), Terlipressin (triglycyl lysine vasopressin (Zuberi, 2007)), Felypressin ([2-Phenylalanine]lysine vasopressin) (Cecanho et al., 2006), Lypressin (lysine vasopressin) and the OT antagonist, Atosiban (Akerlund, 2006), have been approved for clinical use in the US, Canada and/or in Europe. For a review of the use of AVP and its

Conclusion

While OT and AVP agonists, antagonists, radiolabelled and fluorescent ligands have found widespread use as research tools in a wide variety of in vitro and in vivo studies on the peripheral and central effects of these peptides, many investigators continue to use some earlier peptides which lack specificity for a given receptor type.

In this review we have attempted to provide a snapshot of the current state of the art on the available OT and AVP agonists and antagonists for the OT receptor, for

Acknowledgements

Work from the authors’ laboratories was supported in part by research grants from the National Institute of General Medical Sciences (No. GM-25280: Maurice Manning), The Italian Association for Cancer Research (AIRC 2006) and the Carpilo Foundation (Grant 200610882) (Bice Chini), INSERM, Institute de la Santé et de la Recherche Médicale and CNRS (Centre National de la Recherche Scientifique) (Thierry Durroux; Bernard Mouillac; Gilles Guillon). We are greatly indebted to our former colleagues

References (288)

  • N. Cotte et al.

    Identification of residues responsible for the selective binding of peptide antagonists and agonists in the V2 vasopressin receptor

    J. Biol. Chem.

    (1998)
  • A. Cudnoch-Jedrzejewska et al.

    Interaction of AT1 receptors and V1a receptors-mediated effects in the central cardiovascular control during the post-infarct state

    Regul. Pept.

    (2007)
  • M.R. Cumbers et al.

    A neuromodulatory role for oxytocin within the supramammillary nucleus

    Neuropeptides

    (2007)
  • Y. De Keyzer et al.

    Cloning and characterization of the human V3 pituitary vasopressin receptor

    FEBS Lett.

    (1994)
  • C.E. Detillion et al.

    Social facilitation of wound healing

    Psychoneuroendocrinology

    (2004)
  • P. Eggena et al.

    Synthesis and characterization of a long-acting fluorescent analog of vasotocin

    Biol. Cell.

    (1989)
  • J. Elands et al.

    125I-labeled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]OVT: a selective oxytocin receptor ligand

    Eur. J. Pharmacol.

    (1988)
  • A.A. Failli et al.

    Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists

    Bioorg. Med. Chem. Lett.

    (2006)
  • C.F. Ferris et al.

    Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior

    Pharmacol. Biochem. Behav.

    (2006)
  • M. Fragiadaki et al.

    Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7

    Eur. J. Med. Chem.

    (2007)
  • L. Gera et al.

    New bradykinin antagonists having very high potency at B1 receptors

    Immunopharmacology

    (1996)
  • P. Gines

    Vaptans: a promising therapy in the management of advanced cirrhosis

    J. Hepatol.

    (2007)
  • C.D. Guillon et al.

    Azetidinones as vasopressin V1a antagonists

    Bioorg. Med. Chem.

    (2007)
  • G. Guillon et al.

    Fluorescent peptide hormones: development of high affinity vasopressin analogues

    Peptides

    (1992)
  • I. Hansenne et al.

    Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network

    J. Neuroimmunol.

    (2005)
  • S.R. Hawtin et al.

    A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists

    FEBS Lett.

    (2005)
  • E. Hollander et al.

    Oxytocin increases retention of social cognition in autism

    Biol. Psychiatry

    (2007)
  • M. Akerlund

    Targeting the oxytocin receptor to relax the myometrium

    Expert Opin. Ther. Targets

    (2006)
  • J.D. Albright et al.

    5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors

    J. Med. Chem.

    (1998)
  • F. Ali et al.

    Therapeutic potential of vasopressin receptor antagonists

    Drugs

    (2007)
  • M. Andres et al.

    Pharmacological characterization of F-180: a selective human V(1a) vasopressin receptor agonist of high affinity

    Br. J. Pharmacol.

    (2002)
  • F.A. Antoni

    Novel ligand specificity of pituitary vasopressin receptors in the rat

    Neuroendocrinology

    (1984)
  • R. Arban

    V1b receptors: new probes for therapy

    Endocrinology

    (2007)
  • D.M. Ashworth et al.

    Nonpeptide oxytocin agonists

    Drugs Future

    (2006)
  • S.J. Assinder et al.

    Regulation of 5 alpha-reductase isoforms by oxytocin in the rat ventral prostate

    Endocrinology

    (2004)
  • C.J. Aurell et al.

    Development of vasopressor specific vasotocin analogues with prolonged effects

  • K. Bankowski et al.

    Design and synthesis of potent in vivo antagonists of oxytocin

    Int. J. Pept. Protein Res.

    (1980)
  • C. Barberis et al.

    Characterization of a novel, linear radioiodinated vasopressin antagonist: an excellent radioligand for vasopressin V1a receptors

    Neuroendocrinology

    (1995)
  • C. Barberis et al.

    Molecular pharmacology of AVP and OT receptors and therapeutic potential

    Drug News Perspect.

    (1999)
  • L. Belec et al.

    Examination of structural characteristics of the potent oxytocin antagonists [dPen1,Pen6]-OT and [dPen1,Pen6,5-tBuPro7]-OT by NMR, Raman, CD spectroscopy and molecular modeling

    J. Pept. Sci.

    (2005)
  • I.M. Bell et al.

    Development of orally active oxytocin antagonists: Studies on 1-(1-(4-[1-(2-Methyl-1-oxidopyridin-3ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl)piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

    J. Med. Chem.

    (1998)
  • B. Berde et al.

    Basic pharmacological properties of synthetic analogues and homologues of the neurohypophysial hormones

  • C. Bernadich et al.

    Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension

    Hepatology

    (1998)
  • V. Bernier et al.

    Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus

    J. Am. Soc. Nephrol.

    (2006)
  • M. Birnbaumer et al.

    Molecular cloning of the receptor for human antidiuretic hormone

    Nature

    (1992)
  • E.A. Bone et al.

    Rapid accumulation of inositol phosphates in isolated rat superior cervical sympathetic ganglia exposed to V1-vasopressin and muscarinic cholinergic stimuli

    Biochem. J.

    (1984)
  • O.J. Bosch et al.

    Prenatal stress: opposite effects on anxiety and hypothalamic expression of vasopressin and corticotrophin-releasing hormone in rats selectivity bred for high and low anxiety

    Eur. J. Neurosci.

    (2006)
  • O.J. Bosch et al.

    Brain oxytocin correlates with maternal aggression: link to anxiety

    J. Neurosci.

    (2005)
  • A. Buku et al.

    Probes for vasopressin receptors. Attachment of affinity and fluorescent groups in vasopressin

    Int. J. Pept. Protein Res.

    (1990)
  • A. Buku et al.

    Synthesis and characterization of fluorescein- and rhodamine-labeled probes for vasotocin receptors

    Am. J. Physiol.

    (1989)
  • Cited by (239)

    View all citing articles on Scopus

    Dedicated with gratitude to Dr. Wilbur H. Sawyer, Dr. W.Y. Chan, Dr. Serge Jard and Dr. Claude Barberis.

    View full text