+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V 1a, V 1b and V 2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V 1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V 1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V 2/V 1a antagonist, conivaptan and the V 2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V 1a, V 1b and V 2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.

          Related collections

          Most cited references 272

          • Record: found
          • Abstract: not found
          • Article: not found

          Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide

            • Record: found
            • Abstract: found
            • Article: not found

            The oxytocin receptor system: structure, function, and regulation.

             G Gimpl,  F Fahrenholz (2001)
            The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.
              • Record: found
              • Abstract: found
              • Article: not found

              Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine.

              The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia.

                Author and article information

                [* ]Biochemistry and Cancer Biology, University of Toledo College of Medicine Toledo, OH, USA
                []Faculty of Chemistry, University of Warsaw Warsaw, Poland
                []Faculty of Chemistry, Institute of Organic Chemistry, Technical University of Lodz Lodz, Poland
                [§ ]Pharmaceutical Research Institute Warsaw, Poland
                []CNR Institute of Neuroscience Milan, Italy
                [** ]Institut de Genomique Fonctionnelle, UMR5203-CNRS, U661-INSERM, Univ. Montpellier I & II Montpellier, Cedex, France
                Author notes
                Correspondence to: M. Manning, Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA (e-mail: maurice.manning@ ).

                Re-use of this article is permitted in accordance with the Terms and Conditions set out at

                J Neuroendocrinol
                J. Neuroendocrinol
                Journal of Neuroendocrinology
                Blackwell Publishing Ltd (Oxford, UK )
                April 2012
                : 24
                : 4
                : 609-628
                © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Review Articles

                Endocrinology & Diabetes

                non-peptide, agonists, peptide, oxytocin, vasopressin, antagonists


                Comment on this article