The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During ...the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular Ca2+ increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
► Stratification of the groundwater is evidenced through Na and Cl and 18O and 2H. ► Good agreement is observed between 3H/3He and CFC ages. ► Complex mixing processes are evidenced at intermediate ...depth. ► Apparent age distribution suggest exponential or piston flow model. ► Extremely high SF6 concentrations are attributed to the nuclear reactor explosion.
Following the explosion of reactor 4 at the Chernobyl power plant in northern Ukraine in 1986, contaminated soil and vegetation were buried in shallow trenches dug directly on-site in an Aeolian sand deposit. These trenches are sources of radionuclide (RN) pollution. The objective of the present study is to provide constraints for the Chernobyl flow and RN transport models by characterising groundwater residence time. A radiochronometer 3H/3He method (t1/2=12.3a) and anthropogenic tracers including CFC and SF6 are investigated along with the water mass natural tracers Na, Cl, 18O and 2H.
The groundwater is stratified, as evidenced by Na and Cl concentrations and stable isotopes (18O, 2H). In the upper aeolian layer, the Na–Cl relationship corresponds to evapotranspiration of precipitation, while in the underlying alluvial layer, an increase in Na and Cl with depth suggests both water–rock interactions and mixing processes. The 3H/3He and CFC apparent groundwater ages increase with depth, ranging from ‘recent’ (1–3a) at a 2m depth below the groundwater table to much higher apparent ages of 50–60a at 27m depth below the groundwater table. Discrepancies in 3H/3He and CFC apparent ages (20–25a and 3–10a, respectively) were observed during the 2008 campaign at an intermediate depth immediately below the aeolian/alluvial sand limit, which were attributed to the complex water transfer processes. Extremely high SF6 concentrations, well above equilibrium with the atmosphere and up to 1112pptv, are attributed to significant contamination of the soils following the nuclear reactor explosion in 1986. The SF6 concentration vs. the apparent groundwater ages agrees with this interpretation, as the high SF6 concentrations are all more recent than 1985. The persistence of the SF6 concentration suggests that SF6 was introduced in the soil atmosphere and slowly integrated in the groundwater moving along the hydraulic gradient. The apparent age distribution in the lumped parameter models suggests an exponential or piston flow model in the upper geological section, followed by more pronounced mixing processes in the lower section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In mammals, the vasopressin V1b receptor (V1b-R) is known to regulate ACTH secretion and, more recently, stress and anxiety. The characterization of the molecular determinant responsible for its ...pharmacological selectivity was made possible by the recent discovery of the first V1b antagonist, SSR149415. Based upon the structure of the crystallized bovine rhodopsin, we established a three-dimensional molecular model of interaction between the human V1b-R (hV1b-R) and SSR149415. Four amino acids located in distinct transmembrane helices (fourth, fifth, and seventh) were found potentially responsible for the hV1b-R selectivity. To validate these assumptions, we selectively replaced the leucine 181, methionine 220, alanine 334, and serine 338 residues of hV1a-R by their corresponding amino acids present in the hV1b-R (phenylalanine 164, threonine 203, methionine 324, and asparagine 328, respectively). Four mutants, which all exhibited nanomolar affinities for vasopressin and good coupling to phospholipase C pathway, were generated. hV1a receptors mutated at position 220 and 334 exhibited striking increase in affinity for SSR149415 both in binding and phospholipase C assays at variance with the hV1a-R modified at position 181 or 338. In conclusion, this study provides the first structural features concerning the hV1b-R and highlights the role of few specific residues in its pharmacological selectivity.
Located in the northeastern region of Italy, the Venetian Plain (VP) is a sedimentary basin containing an extensively exploited groundwater system. The northern part is characterised by a large ...undifferentiated phreatic aquifer constituted by coarse grain alluvial deposits and recharged by local rainfalls and discharges from the rivers Brenta and Piave. The southern plain is characterised by a series of aquitards and sandy aquifers forming a well-defined artesian multi-aquifer system. In order to determine origins, transit times and mixing proportions of different components in groundwater (GW), a multi tracer study (3
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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