Selective V1a Receptor Antagonist Research Articles

Desmopressin enhances random-pattern skin flap survival in rats: Possible role of vasopressin Type-1a and 2 receptors

BackgroundMany drugs have been explored for their role in improving skin flap survival. 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin) is a synthesized form of anti-diuretic hormone (ADH) and a selective agonist for vasopressin type-2 receptors (V2 receptors). Desmopressin has been shown to improve endothelial function, induce vasodilation, and reduce inflammation. We aimed to evaluate its efficacy in enhancing flap survival and assess the role of vasopressin receptors in this process. Materials and methodsWe randomly assigned six male Wistar rats to each study group. Different doses of desmopressin were injected intraperitoneally to find the most effective amount (8 μg/rat). SR-49059, a selective V1a receptor antagonist, was given at 2μg/rat before providing the most effective dose of desmopressin (8μg/rat). Histopathological assessments, quantitative measurements of interleukin-1β (IL-1β), Tumor necrosis factor-alpha (TNF-α), and Nuclear Factor-κB (NF-κB), optical imaging, and measurement of the expression levels of V2 receptor in the rat skin tissue were performed. ResultsDesmopressin (8μg/rat) significantly reduced the mean percentage of necrotic area compared to the control group (19.35% vs 73.57%). Histopathological evaluations revealed a notable reduction in tissue inflammation, edema, and degeneration following administration of desmopressin (8). The expression of the V2 receptor was increased following desmopressin administration. It also led to a reduction in IL-1β, TNF-α, and NF-κB levels. The protective effect of desmopressin on flap survival was reversed upon giving SR-49059. The optical imaging revealed enhanced blood flow in the desmopressin group compared to the control group. ConclusionsDesmopressin could be repurposed to improve flap survival. V1a and V2 receptors probably mediate this effect.

Temporal patterns in the dependency structures of the cardiovascular time series

Copula density is a function that quantifies the level of dependency between two, or more, related time series, and also visualizes their (non)linear dependency structures. This paper aims to analyze and compare different methods for copula density estimation: local (naïve) estimation, kernel estimation, K nearest neighbors, Markov state approach, histograms, and Voronoi decomposition. The methods are compared by mapping the copula density into a time series (dependency level time series) and applying Sample Entropy estimates over the range of parameters. Application examples include systolic blood pressure and pulse interval signals recorded from conscious laboratory rats, treated either with vasopressin selective V1a and V2 receptor antagonists (100 ng and 500 ng) or with saline (control group). The signals are analyzed using composite multiscale entropy. It is shown that each estimation method suffers from bias, but, for each case, a stable working region can be found. It was also shown that the analysis of the dependency level time series could reveal the information that could not be extracted from the classical beat-to-beat time series, and that the copula density, transformed to real signals domain, visualizes the regions where the dependency of cardiovascular signals is exhibited the most, reflecting their mutual relationship and providing the possibility for further research.

Balovaptan and Autism Spectrum Disorder

Abstract Balovaptan, an antagonist of the vasopressin system, has been shown to be a drug with potential to treat the main symptoms of Autism Spectrum Disorder (ASD). The objective of this work was to gather and analyze information already published about the mechanism of action, clinical trials, dosage information, pharmacokinetics, and safety profile of balovaptan, bringing an update on the current situation of this molecule in ASD. A bibliographic review was conducted through the Embase, PubMed, Science Direct, LILACS, SciELO, Web of Science, Google Scholar, and Cochrane Library databases. Results showed that balovaptan is a potent, selective, and brain-penetrant V1a receptor antagonist that may improve social behaviors and communication. Balovaptan received the Breakthrough Therapy designation from the US Food and Drug Administration. Balovaptan showed a favorable safety profile and good pharmacokinetic parameters in studies using doses that varied from 1.5 to 10 mg orally. Although preliminary results have shown promise, the balovaptan study was terminated because improvement in the core symptoms of ASD was lower than expected. However, further studies with substitute molecules should be encouraged, given the therapeutic potential of vasopressin axis modulation and its implications for social behavior.

Evidence of early vasogenic edema following minor head impact that can be reduced with a vasopressin V1a receptor antagonist

BackgroundDoes minor head impact without signs of structural brain damage cause short-term changes in vasogenic edema as measured by an increase apparent diffusion coefficient (ADC) using diffusion weighted imaging? If so, could the increase in vasogenic edema be treated with a vasopressin V1a receptor antagonist? We hypothesized that SRX251, a highly selective V1a antagonist, would reduce vasogenic edema in response to a single minor head impact. MethodsLightly anesthetized male rats were subjected to a sham procedure or a single hit to the forehead using a closed skull, momentum exchange model. Animals recovered in five min and were injected with saline vehicle (n = 8) or SRX251 (n = 8) at 15 min post head impact and again 7−8 hrs later. At 2 h, 6 h, and 24 h post injury, rats were anesthetized and scanned for increases in ADC, a neurological measure of vasogenic edema. Sham rats (n = 6) were exposed to anesthesia and scanned at all time points but were not hit or treated. Images were registered to and analyzed using a 3D MRI rat atlas providing site-specific data on 150 different brain areas. These brain areas were parsed into 11 major brain regions. ResultsUntreated rats with brain injury showed a significant increase in global brain vasogenic edema as compared to sham and SRX251 treated rats. Edema peaked at 6 h in injured, untreated rats in three brain regions where changes in ADC were observed, but returned to sham levels by 24 h. There were regional variations in the time course of vasogenic edema and drug efficacy. Edema was significantly reduced in cerebellum and thalamus with SRX251 treatment while the basal ganglia did not show a response to treatment. ConclusionA single minor impact to the forehead causes regional increases in vasogenic edema that peak at 6 h but return to baseline within a day in a subset of brain regions. Treatment with a selective V1a receptor antagonist can reduce much of the edema.

Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.

β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-κB signal pathway in murine hearts.

Evidence to date suggests that β-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of β-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5 U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h. In β-arrestin 2 KO mouse hearts, deletion of β-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10−9–10−6 M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-κB signaling and ERK1/2 phosphorylation, whereas knockdown of β-arrestin 2 blocked AVP-induced IL-6 increase, NF-κB activation and ERK1/2 phosphorylation. Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-κB activation and IL-6 production. The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-κB phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2 mg/kg, iv) abolished AVP-induced NF-κB activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V1A receptor-mediated β-arrestin2/ERK1/2/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/β-arrestin 2/ERK1/2/NF-κB signaling pathway.

Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging

SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood–brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed.

Optimisation of pharmacokinetic properties to afford an orally bioavailable and selective V1A receptor antagonist

The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.

Maternal Behaviour is Associated with Vasopressin Release in the Medial Preoptic Area and Bed Nucleus of the Stria Terminalis in the Rat

The neuropeptide arginine vasopressin was recently shown to be an important regulator of female social behaviour, including maternal care and aggression. A key brain site for vasopressin- as well as oxytocin-mediated maternal care is the medial preoptic area (MPOA). Together with the adjacent bed nucleus of the stria terminalis (BNST), these brain regions are considered to form a 'super-region' for maternal behaviour. In the present study, we investigated the vasopressin and oxytocin systems within the MPOA and the BNST during maternal care in lactating rats in more detail. Binding to V1a and oxytocin receptors in the BNST and to oxytocin receptors in the MPOA was increased in lactation. Furthermore, microdialysis revealed that vasopressin release significantly increased (MPOA) or tended to increase (BNST) during different phases of maternal care (i.e. with or without suckling stimulus). In support, manipulations of V1a receptors in the MPOA are known to alter maternal care. We now show that local injection of a selective V1a receptor antagonist bilaterally into the BNST did not affect maternal care, but reduced maternal aggression and tended to lower anxiety-related behaviour. The release of oxytocin did not change in any of the brain regions during maternal care. The results obtained indicate that locally-released vasopressin within the MPOA and the BNST is important for the maintenance of complex maternal behaviours, including maternal care and aggression, respectively.

Role of supraspinal vasopressin neurones in the effects of atrial natriuretic peptide on sympathetic nerve activity

The aim of the present study was to determine if paraventricular-spinal vasopressin neurones participate in the sympatho-inhibitory effects of systemically administered atrial natriuretic peptide (ANP) on renal sympathetic nerve activity (RSNA). Experiments were carried out on male Sprague-Dawley rats anesthetized with 1.3 g/kg urethane. Changes in mean arterial pressure (mm Hg), heart rate (beats per minute) and RSNA (%) were measured following intravenous bolus administration of ANP (250 ng, 500 ng and 5 µg). Intrathecal application of selective V1a receptor antagonist was performed to test for the involvement of supraspinal vasopressin pathways in mediating the effect on sympathetic outflow evoked by intravenous ANP administration. The results obtained demonstrated that both low and high doses of ANP caused renal sympathoinhibition (250 ng; −7.5±1%, 500 ng; −14.2±1%, 5 μg; −16.4±2%), concomitant with vasodilation and bradycardia. After spinal vasopressin receptor blockade, the inhibitory effects of ANP were prevented and there was a small renal sympatho-excitation (250 ng; +1.7±0.2%, 500 ng; +6.1±0.03%, 5 μg; +8.0±0.03%, P<0.05). Therefore, the renal sympathetic nerve inhibition elicited by circulating ANP is dependent on the efficacy of a well established supraspinal vasopressin pathway. Since supraspinal vasopressin neurones without exception excite renal sympathetic neurones, it is suggested that ANP elicits this effect by activating cardiac vagal afferents that inhibit the spinally projecting vasopressin neurones at their origin in the paraventicular nucleus of the hypothalamus.

Deletion of N-type Ca2+ Channel Cav2.2 Results in Hyperaggressive Behaviors in Mice

Voltage-dependent N-type Ca(2+) channels play important roles in the regulation of diverse neuronal functions in the brain, but little is known about its role in social aggressive behaviors. Mice lacking the alpha1B subunit (Ca(v)2.2) of N-type Ca(2+) channels showed markedly enhanced aggressive behaviors to an intruder mouse in the resident-intruder test. The dorsal raphe nucleus (DRN), which contains serotonin neurons, is known to be involved in aggression in animals. We thus examined the DRN neurons in the Ca(v)2.2-deficient (Ca(v)2.2(-/-)) mice. Microinjection of omega-conotoxin GVIA, an N-type Ca(2+) channel-specific blocker, into the DRN of wild type mice resulted in escalated aggression, mimicking the phenotypes of Ca(v)2.2(-/-). Electrophysiological analysis showed increased firing activity of serotonin neurons with a reduced inhibitory neurotransmission in the Ca(v)2.2(-/-) DRN. Ca(v)2.2(-/-) mice showed an elevated level of arginine vasopressin, an aggression-related hormone, in the cerebrospinal fluid. In addition, Ca(v)2.2(-/-) mice showed an increase of serotonin in the hypothalamus. These results suggest that N-type Ca(2+) channels at the DRN have a key role in the control of aggression.

Sustained Elevated Levels of Circulating Vasopressin Selectively Stimulate the Proliferation of Kidney Tubular Cells via the Activation of V2 Receptors

The hypothalamic hormone vasopressin (AVP) has known mitogenic effects on various cell types. This study was designed to determine whether sustained elevated levels of circulating AVP could influence cell proliferation within adult tissues known to express different AVP receptors, including the pituitary, adrenal gland, liver, and kidney. Plasmatic AVP was chronically increased by submitting animals to prolonged hyperosmotic stimulation or implanting them with a AVP-containing osmotic minipump. After several days of either treatment, increased cell proliferation was detected only within the kidney. This kidney cell proliferation was not affected by the administration of selective V1a or V1b receptor antagonists but was either inhibited or mimicked by the administration of a selective V2 receptor antagonist or agonist, respectively. Kidney proliferative cells mostly concerned a subpopulation of differentiated tubular cells known to express the V2 receptors and were associated with the phosphorylation of ERK. These data indicate that in the adult rat, sustained elevated levels of circulating AVP stimulates the proliferation of a subpopulation of kidney tubular cells expressing the V2 receptor, providing the first illustration of a mitogenic effect of AVP via the activation of the V2 receptor subtype.

Conopressin-T from Conus tulipa Reveals an Antagonist Switch in Vasopressin-like Peptides

We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin-like peptide family and displays high sequence homology to the mammalian hormone oxytocin (OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V 1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro7 and Gly9), which are replaced with Leu7 and Val9 in conopressin-T. Whereas conopressin-T binds only to OT and V 1a receptors, an L7P analogue had increased affinity for the V 1a receptor and weak V2 receptor binding. Surprisingly, replacing Gly9 with Val9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V 1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V 1a receptor.

Differences in intermale aggression are accompanied by opposite vasopressin release patterns within the septum in rats bred for low and high anxiety

Several studies suggest a role for arginine vasopressin (AVP), particularly in the lateral septum, in the regulation of intermale aggression. We used intracerebral microdialysis to monitor the local in vivo AVP release within the mediolateral septum of adult male Wistar rats bred for low (LAB) or high (HAB) anxiety-related behaviour during exposure to the resident-intruder test. LAB residents showed a significantly higher level of aggression than HAB residents, as reflected by more time spent with lateral threat, offensive upright and total aggressive behaviour as well as by more attacks and a shorter attack latency. Septal AVP release was significantly decreased in high-aggressive LAB males, while septal AVP release tended to increase in HAB males during resident-intruder test exposure. Moreover, LAB residents showed reduced neuronal activation of the lateral septum, as indicated by fewer c-Fos-positive cells, 1 h after the resident-intruder test. Pharmacological manipulation of the septal AVP system by local application of either synthetic AVP to LAB residents or the selective V1a receptor antagonist d(CH(2))(5)Tyr(Me)AVP to HAB residents did not change the level of aggression. However, application of AVP into the septum enhanced anxiety-related behaviour on the elevated plus-maze in LAB males, while local administration of the V1a receptor antagonist reduced social investigation in HAB males during the resident-intruder test. In conclusion, although AVP release patterns within the septum are dependent on the level of aggression, locally released AVP does not seem to be directly involved in the regulation of aggression, but rather modulates non-aggressive social and anxiety-related behaviours.

Vasotocin and Mesotocin Stimulate the Biosynthesis of Neurosteroids in the Frog Brain

The neurohypophysial nonapeptides vasopressin (VP) and oxytocin (OT) modulate a broad range of cognitive and social activities. Notably, in amphibians, vasotocin (VT), the ortholog of mammalian VP, plays a crucial role in the control of sexual behaviors. Because several neurosteroids also regulate reproduction-related behaviors, we investigated the possible effect of VT and the OT ortholog mesotocin (MT) in the control of neurosteroid production. Double immunohistochemical labeling of frog brain sections revealed the presence of VT/MT-positive fibers in close proximity of neurons expressing the steroidogenic enzymes 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) and cytochrome P450 17alpha-hydroxylase/c17, 20-lyase (P450(C17)). High concentrations of VT and MT receptor mRNAs were observed in diencephalic nuclei containing the 3beta-HSD and P450(C17) neuronal populations. Exposure of frog hypothalamic explants to graded concentrations of VT or MT produced a dose-dependent increase in the formation of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone. The stimulatory effect of VT and MT on neurosteroid biosynthesis was mimicked by VP and OT, as well as by a selective V1b receptor agonist, whereas V2 and OT receptor agonists had no effect. VT-induced neurosteroid production was completely suppressed by selective V1a receptor antagonists and was not affected by V2 and OT receptor antagonists. Concurrently, the effect of MT on neurosteroidogenesis was markedly attenuated by selective OT and V1a receptor antagonists but not by a V2 antagonist. The present study provides the first evidence for a regulatory effect of VT and MT on neurosteroid biosynthesis. These data suggest that neurosteroids may mediate some of the behavioral actions of VT and MT.

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

Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 μg, 20 μg, 2 mg/kg or vehicle. When tested 90–120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.

Comparative Cardiac Effects of Terlipressin, Vasopressin, and Norepinephrine on an Isolated Perfused Rabbit Heart

Terlipressin, a synthetic analog of arginine-vasopressin (AVP), has been proposed as an effective vasopressive therapy in catecholamine-resistant vasodilatory shock. Although beneficial effects of terlipressin on systemic arterial pressure have been clearly demonstrated, its intrinsic effects on coronary circulation and myocardial performances remain unknown. The authors compared the coronary and myocardial effects of terlipressin (1-100 nM, n = 10), AVP (10-1000 pM, n = 10), and norepinephrine (1-100 nM, n = 10) on an erythrocyte-perfused isolated rabbit heart. The cardiac effects of terlipressin were also assessed in erythrocyte-perfused hearts in which the myocardial oxygen delivery was maintained constant and buffer-perfused hearts. Finally, the cardiac effects of terlipressin and AVP were studied in hearts pretreated by [d(CH2)5Tyr(Me)]AVP (0.1 microM), a selective V1a receptor antagonist. Norepinephrine induced a biphasic coronary effect associated with a concentration-dependent increase in myocardial performances. AVP and terlipressin significantly decreased coronary blood flow and impaired myocardial performances from 30 pM and 30 nM, respectively (P < 0.05). The cardiac side-effects of terlipressin were confirmed in buffer-perfused hearts but the maintenance of a constant myocardial oxygen delivery constant abolished its effects on myocardial performances. The cardiac effects induced by terlipressin and AVP were nearly completely abolished on hearts pretreated by [d(CH2)5Tyr(Me)]AVP. On isolated rabbit heart, terlipressin induced a coronary vasopressor effect and in turn myocardial depression only at supratherapeutic concentrations (> or =30 nM). Its effects are mainly mediated via V1a receptors. However, these potential negative side effects on the heart were less pronounced than were those of AVP.

Synthesis and Evaluation of Spirobenzazepines as Potent Vasopressin Receptor Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Preparation of Non‐Peptide, Highly Potent and Selective Antagonists of Arginine Vasopressin V1A Receptor by Introduction of Alkoxy Groups.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Molecular dynamics study of 4-OH-phenylacetyl- D-Y(Me)FQNRPR-NH2 selectivity to V1a receptor.

G protein-coupled receptors relay diverse extracellular signals into cells via a common mechanism, involving activation of cytosol G proteins. The mechanism underlies the actions of approximately 50% of all drugs. In this work, we focus on simulating three protein-ligand complexes of the neurohypophyseal hormone analog 4-OH-phenylacetyl- D-Y(Me)FQNRPR-NH2 (I) with the human V1a, V2 and oxytocin receptors. The peptideI is a potent selective V1a receptor antagonist. To obtain relaxed models of the complexes, the following techniques were used: docking ofI into the vasopressin V1a, V2 and oxytocin receptor models, optimization of the geometry of the resulting complexes and molecular dynamics in a fully hydrated 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphatidylcholine lipid bilayer. The results of the simulations allow us to draw some conclusions about the ligand selectivity to V1aR.