Biological Activity
SSR149415 is an orally active, selective vasopressin V1b receptor antagonist (human/r at Ki in nM = 1.5/1.3/V1b, 91/1050/V1a, 1412/2897/V2, 174/270/OT) th at inhibits 30 nM AVP-induced Ca2+ response in human and r at V1b CHO transfectants (Ki = 1.26/2.0 nM). SSR149415 suppresses AVP-mediated physiological responses in vivo, including corticotropin secretion (1-30 mg/kg p.o. or i.p. in rats) upon exogenous AVP administration (0.3 μg/kg alone or 0.03 μg/kg with 0.1 μg corticoliberin/kg via i.v.), restraint stress-Induced corticotropin secretion (EC50 = 10 mg/kg i.p. in rats), and in a murine model of anxiety (four-plate test; 1-10 mg/kg i.p. or 3-10 mg/kg p.o. acute or 10 mg/kg/day p.o.).
in vivo
Nelivaptan (1-30 mg/kg; 30 min i.p. or 2 h p.o. before an exogenous AVP injection) inhibits exogenous AVP-induced increase in plasma corticotropin in Sprague-Dawley rats[1].
Nelivaptan (1-10 mg/kg; p.o.; 1, 2, 3, 4, and 6 h before the AVP challenge) produces powerful dose-dependent inhibition of the corticotropin increase in response to exogenous AVP plus corticotropin-releasing factor (CRF) in Sprague-Dawley rats[1].
Nelivaptan (1-10 mg/kg; i.p. 30 min or 60 min before test; or p.o. for 7 days) displays anxiolytic-like activity after acute and 7-day repeated administrations in male NMRI mice [1].
Nelivaptan (30 mg/kg; i.p.; daily for two weeks) retains efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked in male Wistar rats with chronic mild stress[2].
| Animal Model: | Male Wistar rats (300-400 g, aged 3 months) with chronic mild stress[2] |
| Dosage: | 30 mg/kg |
| Administration: | Intraperitoneal injection (i.p.); daily for two weeks |
| Result: | Chronic administration reversed learned helplessness and anhedonia even when methylazoxymethanol (MAM) was administered.
Attenuated these depressive-like behaviors after 1 week.
Restored the density of Ki-67-positive cells to control levels.
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| Animal Model: | Male Sprague-Dawley CD rats (275-300 g)[1] |
| Dosage: | 1, 3, 10, 30 mg/kg |
| Administration: | Intraperitoneal injection (i.p.) or Oral gavage (p.o.); 30 min i.p. or 2 h p.o. before an exogenous AVP injection |
| Result: | Antagonized AVP-induced corticotropin secretion in a dose-dependent manner by both intraperitoneal and oral routes.
The inhibition was significant from 10 mg/kg p.o. and 3 mg/kg i.p. upwards.
The inhibitory action lasted significantly for more than 2 h at 10 mg/kg i.p. and up to 4 h at 10 mg/kg p.o..
Had no effect on basal corticotropin plasma levels up to 30 mg/kg p.o..
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| Animal Model: | Male Sprague-Dawley CD rats (275-300 g)[1] |
| Dosage: | 1, 3, 10 mg/kg |
| Administration: | Oral gavage (p.o.); 1, 2, 3, 4, and 6 h before the AVP challenge (10 mg/kg) |
| Result: | Produced powerful dose-dependent inhibition of the corticotropin increase in response to exogenous AVP plus corticoliberin; the effect was significant from the dose of 3 mg/kg p.o.. Complete blockade was achieved at 10 mg/kg.
Showed a fast onset of action, the inhibitory effect was maximal at 1 h after administration.
The inhibitory effect on corticotropin secretion lasted significantly more than 4 h, demonstrating a long-lasting oral effect in a specific V1b-related model.
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| Animal Model: | Male NMRI mice (20 g)[1] |
| Dosage: | 1, 3, 10 mg/kg |
| Administration: | Intraperitoneal injection (i.p.) or Oral gavage (p.o.); i.p. (1, 3, 10 mg/kg) 30 min or 60 min befeore; p.o. (10 mg/kg) for 7 days, |
| Result: | In the acute experiments, i.p. and p.o. compound increased the number of punished crossings showing marked anxiolytic effects.
Post hoc analysis revealed that these effects reached statistical significance from 3 mg/kg p.o. and i.p.
The anxiolytic-like activity was still significantly maintained when given repeatedly at 10 mg/kg p.o. for 7 days.
The oral time course of the anxiolytic-like action performed at 10 mg/kg indicated that effects lasted for more than 4 h.
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![(2S,4R)-1-[(R)-5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide Structure](https://www.chemicalbook.com/CAS/GIF/439687-69-1.gif)
