L-368,899 hydrochloride

L-368,899 is an orally active and selective OT (oxytocin ) receptor antagonist, with IC50s of 8.9 and 26 nM for uterus of rat and human, respectively. L-368,899 can cross the blood-brain barrier (BBB). L-368,899 inhibits oxytocin-stimulated uterine contractions in rats and can be used in study of preterm labor[1][2][3].

Research Areas >> Endocrinology

Signaling Pathways >> GPCR/G Protein >> Oxytocin Receptor

IC50: 8.9 nM (rat uterus), 26 nM (human uterus)[3].

L-368,899 (0.1, 0.3, 1 mg/kg; infused i.v.; single) shows a dose-related antagonism of OT-stimulated uterine contractions with an AD50 value of 0.35 mg/kg in vivo[1]. L-368,899 (3, 10, 30 mg/kg; i.d.; single) inhibits the contractile effects of OT (AD50= 7 mg/kg) with a long (>4 h) duration of action in vivo (AD50: the dose of L-368,899 required to reduce the response to OT by 50%)[1]. L-368,899 (10 mg/kg, p.o.; single) shows bioavailability (AUC 0-6 h) of 35%[1]. L-368,899 (0.54, 1.8, 5.4 mg/kg; i.v.; single) reduces both oxytocin-induced and endogenous increases in plasma PGFM concentration[2]. Animal Model: Adult female Sprague-Dawley rats (250-350 g)[1]. Dosage: 0.1, 0.3, 1 mg/kg Administration: Infused intravenous injection; single. Result: Inhibited OT-stimulated uterine contractions with an AD50 value of 0.35 mg/kg. Animal Model: Adult female Sprague-Dawley rats (250-350 g)[1]. Dosage: 3, 10, 30 mg/kg Administration: Intraduodenal; single. Result: Exhibited a antagonism of OT-stimulated uterine contractions with an AD50 of 7 mg/kg and duration of action more than 4 h. Animal Model: Adult female Sprague-Dawley rats (250-350 g)[1]. Dosage: 10 mg/kg Administration: Oral administration, single. Result: Showed orally active with bioavailability (AUC 0-6 h) of 35%. Animal Model: Mature Dorset cross ewes (53-57 kg; Removal of ovaries)[2]. Dosage: 0.54, 1.8, 5.4 mg/kg (3, 10 and 30 µg/kg/min for 3 h; dissolved in 0.9% saline). Administration: Intravenous infusion; single. Result: Led to a significant decrease in both the frequency (from 2.2 to 1.0 episodes/ewe) and amplitude (from 68.8 to 31.8 pg/mL) of episodes of increased plasma concentration of PGFM.

[1]. Pettibone D J, et al. L‐368,899, a potent orally active oxytocin antagonist for potential use in preterm labor[J]. Drug development research, 1993, 30(3): 129-142.

[2]. Mann GE, et al. Attenuation of PGF2alpha release in ewes infused with the oxytocin antagonist L-368,899. Domest Anim Endocrinol. 2003 Oct;25(3):255-62.

[3]. Williams PD, et al. 1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor. J Med Chem. 1994 Mar 4;37(5):565-71.