L-368,899 is a potent, orally bioavailable, non-peptide oxytocin receptor antagonist.

L-368,899 shows IC50s of 8.9 nM and 26 nM for rat uterus and human uterus oxytocin receptor, respectively. Additionally, L-368,899 is less active on VP receptor in human liver and kidney, rat liver and kidney. The IC50 values are 510 nM, 960 nM, 890 nM, 2400 nM, respectively.

L-368,899 exhibits similar pharmacokinetics in rats and dogs. After a single iv. injection, L-368,899 had a t1/2 of 2 hr in both species. Additionally, L-368,899 has a plasma clearance between 23 and 36 ml/min/kg in rats or dogs. L-368,899 exhibits Vdss values of 2.0 and 2.6 liters/kg and 3.4 to 4.9 liters/kg for dogs, respectively.
L-368,899 is orally available. In the rat, at the 5 mg/kg dose, the oral bioavailabilities are 14% and 18% for female and male rats, respectively. Additionally, the oral bioavailabilities are 17% and 41% for female and male rats, respectively at the dosage of 25 mg/kg.

L-368,899 is a full antagonist of OXTR through all OXTR -dependent messenger systems.

L368,899 can crosses the blood-brain barrier. Additionally, it accumulates in brain areas implicated in social behavior and may diminish social motivation. Moreover, the compound has been
successfully used to alter OXTR mediated behaviors following systemic administration in mouse studies.

In social isolation-induced aggression in mice models pathological human aggression. L-368,899 at a dosage of 10 mg/kg causes a similar partial blockade of oxytocin (OXT) effects on distance traveled. While TGOT (OXTR agonist TGOT) at the highest dose appeared to be having some impact on aggression.

L-368,899 has been shown to specifically inhibit the OT receptor in mammals. Additionally, it also affects two zebrafish receptors for zOT (Oxtr and Oxtrl). However, it has no effects on the two (zebrafish vasopressin) zVP-1 receptors. The antagonist decreases social preference in adult and larval zebrafish. But not affect anxiety in adults.

In conclusion, L-368,899, as an oxytocin receptor antagonist, might be a very useful tool to investigate the involvement of endogenous oxytocin in primate social behavior.


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[2]. Maria L Boccia, et al. Horm Behav. 2007 Sep;52(3):344-51