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The human V1b receptor (V1bR) is primarily expressed in the corticotropic cells of the anterior pituitary where it is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The activation of V1bR induces the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary cells which, in turn, stimulates the production of cortisol via the adrenal cortex. Clinical studies have demonstrated the chronic dysfunction of the HPA axis in patients with several psychiatric disorders. Thus, the inhibition of the V1b receptor and normalizing the HPA axis hyperactivity is a promising approach to the treatment of many stress-related disorders such as anxiety and depression. Nelivaptan is a selective V1bR antagonist that can be used for this purpose and an excellent molecule to study how antagonists interact with V1bR, especially since in recent years the experimental structures of vasopressin V2 and oxytocin receptors were solved, providing high-similarity templates for homology modeling of V1bR. Therefore, in this work, six independent molecular dynamics simulations of a V1bR-nelivaptan complex in a fully hydrated lipid bilayer, yielding a total simulation time of 6.0 μs, have been conducted. In the lowest-energy complexes obtained in this work and proposed to be the most probable structure of the V1bR-nelivaptan complex, the location of the ligand inside the receptor pocket is very similar to that of the other ligands observed in the experimental structures of the vasopressin/oxytocin receptor family. The receptor-ligand interaction has been analyzed and described, revealing the details of the molecular mechanism of this antagonist binding to V1bR and a probable contribution of L200 5×40 and T203 5×43 to binding selectivity., (© 2024 Wiley Periodicals LLC.)

The vasopressin V 2 receptor (V 2 R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V 2 R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-V 2 R interactions, potentially aiding the design of novel antagonists for V 2 R and other G protein-coupled receptors., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V 2 receptor (V 2 R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V 2 R antagonists, but not their affinity, was correlated with the efficacy in both ex vivo and in vivo models of ADPKD. We envision that the kinetics-directed drug candidate selection and development may have general applicability for ADPKD and other therapeutic areas as well.

We have developed two ligand- and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained quantitative structure activity relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (E H2O ), the polarizability (P), and the calculated partial charge on atom N7 (q6) of the common substructure. The first two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures was also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identified with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and molecular dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traditional Chinese medicines (TCMs) have been a rich source of novel drug discovery, and Cassia seed is one of the common TCMs with numerous biological effects. Based on the existing reports on neuroprotection by Cassia seed extract, the present study aims to search possible pharmacological targets behind the neuroprotective effects of the Cassia seeds by evaluating the functional effect of specific Cassia compounds on various G-protein-coupled receptors. Among the four test compounds (cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, and 2-hydroxyemodin 1-methylether), only aurantio-obtusin demonstrated a specific V 1A R antagonist effect (71.80 ± 6.0% inhibition at 100 µM) and yielded an IC 50 value of 67.70 ± 2.41 μM. A molecular docking study predicted an additional interaction of the hydroxyl group at C6 and a methoxy group at C7 of aurantio-obtusin with the Ser341 residue as functional for the observed antagonist effect. In the transient brain ischemia/reperfusion injury C57BL/6 mice model, aurantio-obtusin attenuated the latency time that was reduced in the bilateral common carotid artery occlusion (BCCAO) groups. Likewise, compared to neuronal damage in the BCCAO groups, treatment with aurantio-obtusin (10 mg/kg, p.o.) significantly reduced the severity of damage in medial cornu ammonis 1 (mCA1), dorsal CA1, and cortex regions. Overall, the findings of this study highlight V 1A R as a possible target of aurantio-obtusin for neuroprotection.

Background and Purpose: We investigated the inhibitory effect and associated molecular mechanisms of tolvaptan on angiotensin II (AngII)-induced aldosterone production in vitro and in vivo., Experimental Approach: In vitro, H295R human adrenocarcinoma cells were incubated with 1 μmol·L -1 arginine vasopressin (AVP) or dDAVP, or tolvaptan (0.1, 1, and 3 μmol·L -1 ) in the presence and absence of 100 nmol·L -1 of AngII. In vivo, Sprague-Dawley rats were treated with tolvaptan 0.05% in the diet for 6 days in the presence and absence of 200 pmol·min -1 AngII., Key Results: Tolvaptan suppressed AngII-induced aldosterone production in a dose-dependent manner in H295R cells, whereas neither AVP nor dDAVP in the presence or absence of AngII altered aldosterone production, suggesting the vasopressin V 2 receptor was not involved in the inhibitory effect of tolvaptan on aldosterone synthesis. In addition, tolvaptan inhibited the AngII-induced increase in aldosterone synthase (CYP11B2) protein levels without suppressing CYP11B2 mRNA expression. Notably, tolvaptan increased the levels of unfolded protein response (UPR) marker DDIT3 and eIF2α phosphorylation (a UPR-induced event), which could block the translation of CYP11B2 mRNA into protein and thereby inhibit aldosterone production. In vivo, tolvaptan significantly inhibited AngII-induced increases in serum and adrenal aldosterone levels and CYP11B2 protein levels. This anti-aldosterone effect was associated with a reduction in the elevated systolic and diastolic BP., Conclusions and Implications: Tolvaptan inhibited AngII-stimulated aldosterone production via a V 2 receptor-independent pathway, which can counteract or even surpass its potential activating effect of diuresis-induced aldosterone secretion in certain aldosterone-mediated pathological conditions., (© 2019 The British Pharmacological Society.)

Vasotocin 1a and 1b receptors (V1aR and V1bR) have been shown to play important roles in the neuroendocrine regulation of stress responses via the anterior pituitary (AP) of birds. To identify effective subtype-specific antagonists for the chicken V1aR (cV1aR) and cV1bR, potential antagonists to the mammalian V1R were screened against the cV1aR and cV1bR 3D structural models by molecular docking analysis with determination of binding pocket/amino acid residues involved in the interaction. The antagonistic effects of the selected ligands were examined by measuring pro-opiomelanocortin (POMC) heteronuclear RNA (hnPOMC) levels following the in vitro stress administration to primary chicken AP cells. Results of in silico analysis showed that the Manning compound and several other antagonists were bound to cV1bR with higher affinity than the natural agonist, arginine vasotocin (AVT). Similarities and differences in the antagonist-receptor binding interface with receptors were characterized for each ligand. Non-peptide mammalian V1bR antagonists, SSR-149415 and L-368899, were shown to be effective and had an additive effect in blocking POMC hnRNA expression in pituitary cell culture studies. SR-49059 antagonized the effect(s) of AVT/CRH on the downregulation of the cV1aR and the upregulation of the cCRH-R2 expression but not the cV1bR and cCRH-R1. The Manning compound antagonized the downregulation of cV1aR, cV1bR and cCRH-R1 and the upregulation of cCRH-R2 expression. The specificity of antagonists apparently resulted from unique differences in the interacting residues and their binding affinities. Collectively, these results provide valuable leads for future development of novel compounds capable of blocking or attenuating the AP stress response of avian species and perhaps other non-mammalian vertebrates as well.

The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease. To get structural insights related to V2R-ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three-dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies. The theoretical results show that binding recognition of these ligands on V2R is diverse, but the main pharmacophore (electronic and π-π interactions) is maintained; thus, this information was validated under QSAR results. QSAR studies were performed using MLR analysis followed by ANN analysis to increase the model quality. The final equation was developed by choosing the optimal combination of descriptors after removing the outliers. The applicability domains of the constructed QSAR models were defined using the leverage and standardization approaches. The results suggest that the proposed QSAR models can reliably predict the reproductive toxicity potential of diverse chemicals, and they can be useful tools for screening new chemicals for safety assessment., (© 2017 John Wiley & Sons A/S.)

Pharmacoperones are small molecules that diffuse into cells and rescue misfolded, mistrafficked protein mutants, restoring their function. These substances act with high target specificity, serving as templates to fold (or refold) receptors, enzymes, ion channels or other proteins and enable them to pass the scrutiny of the cellular quality control system ("rescue"). In the present study we demonstrate that a rescued mutant (L83Q) of the vasopressin type 2 receptor (V2R), shows a strong bias for Gs coupling unlike the WT V2 receptor, which couples to both Gs and Gq/11. Failure of the mutant to couple to Gq/11 was not due to a limiting quantity of G-proteins since other Gq/11-coupled receptors (WT V2R, histamine receptor and muscarinic receptor) responded appropriately to their ligands. Transfection with DNA encoding Gq enabled the V2 receptor mutant to couple to this G protein, but only modestly compared with the WT receptor. Fourteen V2R mutant pharmacoperones, of multiple chemical classes, obtained from a high throughput screen of a 660,000 structure library, and one V2R peptidomimetic antagonist rescues L83Q. The rescued mutant shows similar bias with all pharmacoperones identified, suggesting that the bias is intrinsic to the mutant protein's structure, rather than due to the chemical class of the pharmacoperone. In the case of V2R mutant Y128S, rescue with a pharmacoperone revealed constitutive activity, also with bias for Gs, although both IP and cAMP were produced in response to agonist. These results suggest that particular rescued receptor mutants show functional characteristics that differ from the WT receptor; a finding that may be important to consider as pharmacoperones are developed as therapeutic agents.

Pharmacoperones rescue misrouted mutants of the vasopressin receptor type 2 (V2R) and enable them to traffic to the correct biological locus where they function. Previously, a library of nearly 645,000 structures was interrogated with a high throughput screen; pharmacoperones were identified for V2R mutants with a view toward correcting the underlying mutational defects in nephrogenic diabetes insipidus. In the present study, an orthologous assay was used to evaluate hits from the earlier study. We found no consistent relation between antagonism or agonism and pharmacoperone activity. Active pharmacoperones were identified which had minimal antagonistic activity. This increases the therapeutic reach of these drugs, since virtually all pharmacoperone drugs reported to date were selected from peptidomimetic antagonists. Such mixed-activity drugs have a complex pharmacology limiting their therapeutic utility and requiring their removal prior to stimulation of the receptor with agonist., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Molecular-dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2 -receptor (V2 R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site. The contacts found for the orthosteric site satisfy all the requirements deduced from mutagenesis experiments. Metadynamics simulations for V2 R and its V1a R-analog give an excellent correlation with experimental binding free energies by assuming that the most stable binding site in the simulations corresponds to the experimental binding free energy in each case. The resulting three-site mechanism separates agonists from antagonists and explains subtype selectivity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: The vasopressin V1a and V1b receptors are involved in many crucial physiological, reproductive, behavioral and social functions. Consequently, they are also involved in several pathological conditions, thus the ligands capable of selective stimulation/inhibition of these receptors may present therapeutic benefit in a variety of diseases., Areas Covered: In this review, the author focuses on the vasopressin V1a and V1b receptors, their biological functions and agonists and antagonists patented in the years 2012 - 2014. This paper is divided according to both the target receptor and the applicant and describes the compounds from the patents along with their biological activity., Expert Opinion: In the recent years, pharmaceutical companies have discovered and patented new compounds which act through vasopressin V1a and/or V1b receptors, both peptide and non-peptide. Among the V1bR antagonists published in the last years, the oxindole derivatives appear to be the most promising drug candidates.

From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

Background and Purpose: Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325., Experimental Approach: We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models., Key Results: Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats)., Conclusion: TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents., (© 2014 The British Pharmacological Society.)