Disease relevance of Relcovaptan

• DESIGN: The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion [1].
• In contrast, the V(1A) receptor selective antagonist, SR 49059, and the V(2) receptor selective antagonist, SR 121463A, did not potently inhibit oxytocin-induced [Ca(2+)](i) increase and hyperplasia [2].
• The administration of SR 49059 significantly reduced cerebral vasospasm [3].
• After single and repeated iv or icv administration, we studied the antiemetic properties of SR 49059 on cisplatin-induced emesis in piglets [4].
• Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease [5].

High impact information on Relcovaptan

• Furthermore, SR 49059 inhibited AVP-induced human platelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21268 was inactive up to 20 microM [6].
• SR 49059 showed high affinity for V1a receptors from rat liver (Ki = 1.6 +/- 0.2) and human platelets, adrenals, and myometrium (Ki ranging from 1.1 to 6.3 nM) [6].
• We now show that the cell surface expression and function (binding of the agonist) of the mainly ER-retained wild-type murine vasopressin V2 receptor GFP fusion protein (mV2R.GFP) is restored by the vasopressin receptor antagonists SR49059 and SR121463B with EC50 values similar to their KD values [7].
• The F225C, F308C, and K128C mutants of the V1a receptor were expressed in COS-7 or Chinese hamster ovary cells, and their pharmacological properties toward SR49059 and its sulfydryl-reactive analogues were analyzed [8].
• To identify the binding site of the human V1a vasopressin receptor for the selective nonpeptide antagonist SR49059, we have developed a site-directed irreversible labeling strategy that combines mutagenesis of the receptor and use of sulfydryl-reactive ligands [8].

Chemical compound and disease context of Relcovaptan

• Intravenous bolus injections of 10 pmol/kg body weight of vasopressin (Period 1) and of 50 pmol/kg body weight of oxytocin (Period 2) were given 1 h before and 1, 2 and 4 h after oral administration of 0 (placebo), 25, 75 or 200 mg of SR 49059 [9].
• Dimethyl sulfoxide (DMSO) is widely used as a solvent for other drugs, i.e., for the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) and the V1a receptor-antagonist SR49059, to reduce brain edema [10].

Biological context of Relcovaptan

• Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors [8].
• This raises the possibility that, instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2R by preventing its endocytosis [11].
• In patients, SR49059 decreased 24- h urine volume (11.9 +/- 2.3 to 8.2 +/- 2.0 L; P = 0.005) and water intake (10.7 +/- 1.9 to 7.2 +/- 1.6 L; P < 0.05) [12].
• Effects of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist, on vasopressin-induced vasoconstriction in humans [13].
• CONCLUSION: SR 49059 given orally once a day for 7 days to patients with RP showed favourable effects compared with placebo on finger systolic pressure and temperature recovery after cold immersion, without inducing side-effects [14].

Anatomical context of Relcovaptan

• Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems [12].
• In addition, the 300-mg dose of SR 49059 completely blocked the vasoconstriction of the radial artery induced by AVP [13].
• Moreover, SR 49059 fully inhibited Swiss 3T3 fibroblast proliferation since it completely blocked AVP-stimulated 3T3 cell growth from the G1/G0 into the S/G2M phase, as evidenced by cell cycle analysis using a cytofluorometer [15].
• In summary, SR 49059, through direct interaction at AVP V1a receptors, exerts the most potent antiproliferative effect yet described for any V1a antagonist on Swiss 3T3 cells [15].
• In this study the effect of the novel non-peptide vasopressin V1a receptor antagonist SR 49059 on human internal mammary arteries was investigated [16].

Associations of Relcovaptan with other chemical compounds

• In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH [1].
• Pretreatment with SR 49059 (1 mg/kg I.V.) and SR 27417 (a platelet-activating factor receptor antagonist) (1 mg/kg I.V.) had no effect on the DDAVP-induced (1 microg/kg I.V.) increases in FVIII, vWF and t-PA plasma levels [17].
• Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively) [18].
• Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059 [18].
• The selective non-peptide AVPA SR 49059 blocked the response to both peptides in a similar manner, whilst the non-peptide OTA L367,773 did not block OT-induced increases in seminiferous tubule contractility at doses that were slightly inhibitory to AVP-induced responses [19].

Gene context of Relcovaptan

• A radioligand binding study showed that SR49059 and OPC-21268 potently inhibited [3H]AVP binding to the cloned mouse V1a receptor, with Ki values of 27 and 510 nM, respectively, whereas SSR149415 potently inhibited [3H]AVP binding to the cloned mouse V1b receptor with a Ki value of 110 nM [20].
• 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 [5].
• 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 [5].
• 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively) [21].
• Pharmacological characterization of the transfected human AVP receptors was undertaken by measuring the relative ability of nonpeptide AVP receptor antagonists, YM087, OPC-21268, OPC-31260, SR 49059 and SR 121463A, to inhibit binding of [3H]-AVP [22].

Analytical, diagnostic and therapeutic context of Relcovaptan

• In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity [6].
• In the main study, the potency and efficacy of SR 49059 to block the AVP-induced changes in skin blood flow were assessed in 12 healthy men with a double-blind, triple crossover study design [13].
• Nine pigs were intraabdominally insufflated with CO2 and eight were intraabdominally insufflated with argon; eight pigs received an i.v. injection of 1 mg/kg SR 49059, a VP antagonist, before CO2 insufflation; and six pigs received SR 49059 alone [23].
• After SAH induction, the diameter of the basilar artery in SR 49059-treated groups decreased by only 22% (at 1 h) and by 3% (at 2 days) compared with the control group (P < 0.01) [3].
• The activity in the relcovaptan-treated women remained low, whereas in the placebo group inhibited uterine contractions were observed only in women receiving 'rescue' tocolytic treatment [24].

References