deamino-arginine-vasopressin and carbetocin

Oxytocin (OT) and vasopressin (AVP) mediate their biological actions by acting on four known receptors: The OT (uterine) and the AVP V(1a) (vasopressor), V(1b) (pituitary), V(2) (renal) receptors and a fifth putative AVP V(1c)? (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 Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands.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 V(1b) 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, V(2) agonist), terlipressin (V(1a) agonist), felypressin (V(1a) agonist) and atosiban (Tractocile OT antagonist) are also in clinical use. Despite much early promise, no non-peptide V(1a) or OT antagonists are currently in clinical trials. While a number of orally active non-peptide V(2) antagonists (Vaptans); notably, Tolvaptan, Lixivaptan and Satavaptan, are currently in Phase III clinical trials; to date, only the mixed V(2)/V(1a), 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 V(1b) and OT antagonists, as well as non-peptide V(2) and OT agonists are now in pre-clinical development.

Topics: Animals; Antidiuretic Agents; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Clinical Trials as Topic; Deamino Arginine Vasopressin; Female; Humans; Hyponatremia; Lypressin; Oligopeptides; Oxytocin; Peptides; Rats; Receptors, Oxytocin; Receptors, Vasopressin; Structure-Activity Relationship; Terlipressin; Uterus; Vasodilator Agents; Vasopressins

Recent clinical and pre-clinical research suggests that affective biases may play an important role in the development and perpetuation of mood disorders. Studies in animals have also revealed that similar neuropsychological processes can be measured in non-human species using behavioural assays designed to measure biases in learning and memory or decision-making. Given the proposed links between hormones and mood, we used the affective bias test to investigate the effects of different hormone treatments in both male and female rats. Animals were pre-treated with acute doses of hormone or vehicle control prior to learning each of two independent substrate-reward associations. During a subsequent choice test, positive or negative biases were observed by animal's preference towards or away from the substrate learnt during drug treatment respectively. In both sexes, oestradiol and the oestrogen-like compound bisphenol A induced positive biases, whilst blockade of oestrogen hormones with formestane induced a negative bias. Progesterone induced a negative bias in both sexes, but testosterone only induced a negative bias in males. Blocking testosterone with flutamide induced a positive bias in both sexes at the higher dose (10 mg/kg). The oxytocin analogue, carbetocin induced positive biases in both sexes but the vasopressin analogue, desmopressin, induced a positive bias in male rats only. These results provide evidence that modulating levels of hormones using exogenous treatments can induce affective biases in rats. They also suggest that hormone-induced affective biases influence cognitive and emotional behaviour and could have longer-term effects in some mood disorders.

Topics: Affect; Androstenedione; Animals; Behavior, Animal; Benzhydryl Compounds; Deamino Arginine Vasopressin; Estradiol; Female; Flutamide; Hormones; Male; Oxytocin; Phenols; Progesterone; Rats; Rats, Sprague-Dawley; Sex Factors; Testosterone

Oxytocin (OT) and arginine vasopressin (AVP), in their capacities as neuromodulators, are believed to play an important role in mood control, including regulation of the anxiety response. In the present study, the contributions of oxytocin and vasopressin receptor modulation to anxiety-like behaviors were examined in male Sprague-Dawley rats. The behavioral effects of the OT receptor agonist, carbetocin (intracerebroventricular, intravenous and intraperitoneal routes), the AVP receptor agonist desmopressin (intravenous route), and the OT/AVP(1A) receptor antagonist atosiban (intravenous route) were evaluated in the elevated plus maze. The benzodiazepine diazepam was included as a positive control. Central but not systemic administration of carbetocin produced pronounced anxiolytic-like behavioral changes comparable to those measured following systemic diazepam treatment. The anxiolytic efficacy of carbetocin was maintained following 10 days of once-daily treatment, contrasting with the effects of diazepam which were no longer distinguishable from saline treatment. Systemic administration of desmopressin produced anxiogenic-like effects whereas systemic atosiban produced anxiolytic-like effects. Co-administration of desmopressin with atosiban resulted in saline-like behavioral responses, implicating an AVP(1A) receptor mechanism in the anxiolytic and anxiogenic effects of these neuropeptides following systemic administration. A peripherally-mediated antidiuretic effect of desmopressin on water consumption was also demonstrated. These results highlight the potential therapeutic utility of AVP(1A) receptor blockade in the modulation of anxiety-related behaviors; AVP(1A) receptor blockade appears to be a more promising pharmacological target than does OT receptor activation following systemic drug administration.

Topics: Animals; Anti-Anxiety Agents; Deamino Arginine Vasopressin; Diazepam; Ligands; Male; Maze Learning; Oxytocin; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Receptors, Vasopressin; Vasotocin

The successful coupling of capillary electrochromatography (CEC) to an ion trap mass spectrometer via a nanoelectrospray interface (nESI) is described. Using a conductively coated tip butted to the end of a CEC column, it was possible to obtain a stable spray without any sheath liquid being employed. Selected small peptides were separated with CEC columns (100 microm i.d./25 cm long) packed with 3 microm Hypersil C8 or C18 bonded silica particles with an eluent composed of ammonium acetate/acetonitrile. Peptide mixtures of desmopressin, peptide A, oxytocin, carbetocin and [Met(5)]-enkephalin were detected in the mid-attomole range, which is the lowest amount analyzed using CEC combined with MS detection. It was also observed that sensitivity can be compromised at higher separation voltages. We demonstrate that CEC/nESI-MS, at the current stage of development, represents one of the most sensitive systems for peptide analysis.

Topics: Amino Acid Sequence; Chromatography; Deamino Arginine Vasopressin; Enkephalin, Methionine; Mass Spectrometry; Oncogene Protein pp60(v-src); Oxytocin; Peptide Fragments; Peptides; Quality Control; Sensitivity and Specificity