Osanetant targets the neurokinin-3 (NK3) receptor, a G-protein-coupled receptor that binds neurokinin B (NKB). As a selective NK3 receptor antagonist, it blocks NKB-mediated signaling, which is involved in the regulation of dopamine and other neurotransmitters in the brain. NK3 antagonism has been shown to modulate CNS function and produce antipsychotic and anxiolytic effects.

In vitro, Osanetant acts as a selective NK3 receptor antagonist. It produces anxiolytic- and antidepressant-like effects in preclinical models. Its in vitro activity is assessed using receptor binding assays and functional assays measuring NKB-induced signaling in cells expressing the NK3 receptor.

The oral drug osanetant (SR142801; 1–10 mg/kg; taken 60 minutes prior to testing) dramatically lengthens the duration of social interactions [1]. Immobility time is shortened by oasanetant (ip; 5 and 10 mg/kg; 30 minutes prior to testing) [1].

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In vivo activity of Osanetant has been demonstrated in preclinical models of schizophrenia, depression, and anxiety. It produces anxiolytic- and antidepressant-like effects. Its potential therapy for schizophrenia, depression, and visceral pain has been investigated. The compound was under development for the treatment of schizophrenia and other CNS disorders.

The in vitro receptor binding assay for Osanetant involves measuring its affinity for the NK3 receptor using radioligand binding techniques. These assays use membrane preparations from cells expressing the NK3 receptor and measure the displacement of a labeled ligand by the compound. The compound's selectivity for NK3 over other neurokinin receptors (NK1 and NK2) is also assessed.

In vitro cellular assays for Osanetant are performed using cells expressing the human NK3 receptor. These assays measure the compound's ability to antagonize NKB-induced signaling, such as calcium mobilization or inositol phosphate accumulation. The compound's selective NK3 antagonism is demonstrated by its ability to inhibit NKB-mediated effects without affecting NK1 or NK2 receptors.

Animal/Disease Models: 7weeks old male gerbil (50-60 g) [1]
Doses: 1, 3 and 10 mg/kg
Route of Administration: Po; 60 minutes before testing
Experimental Results: Significant increase in social interaction time.

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In vivo animal studies for Osanetant are conducted in models of schizophrenia, depression, and anxiety. These studies typically involve administration of the compound, followed by assessment of behavioral endpoints such as prepulse inhibition, forced swim test, or elevated plus maze. The compound's anxiolytic- and antidepressant-like effects are evaluated in these models.

Pharmacokinetic properties of Osanetant are characterized by oral administration and systemic bioavailability. As a CNS-active compound, it is designed to cross the blood-brain barrier and reach therapeutic concentrations in the brain. Its pharmacokinetic profile supports its development for the treatment of schizophrenia and other CNS disorders.

Toxicology studies of Osanetant have been conducted to support its clinical development. As an NK3 receptor antagonist, its toxicology profile includes effects on the central nervous system and endocrine function. Preclinical toxicology studies include acute and repeat-dose toxicity assessments, as well as evaluations of CNS and reproductive safety.

[1]. Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils. Pharmacol Biochem Behav. 2006 Apr;83(4):533-9.

Oxanetainetan (SR-142801), developed by Sanofi-Aventis (formerly Sanofi-Sendrab), is an NK3 receptor antagonist that was initially developed for the treatment of schizophrenia and other central nervous system (CNS) disorders. In August 2005, during a review of its portfolio of research and development, the company announced it would discontinue further development of oxanetainetan. This followed the company's decision to discontinue development of eplerenserine for the treatment of schizophrenia. Oxanetainetan is a highly bioavailable, oral, blood-brain barrier-crossing, non-peptide neurokinin/tachykinin 3 receptor (NK1 receptor; NK3R; NK-3R) antagonist, potentially used to treat vasomotor symptoms (VMS) in menopausal women and men undergoing androgen deprivation therapy (ADT), and to inhibit the production of certain hormones. After oral administration, oxanelenthal targets and competitively binds to NK3R in the central nervous system (CNS), thereby blocking its activity and inhibiting NK3R-mediated signal transduction, potentially preventing certain menopausal symptoms, such as hot flashes and vasomotor symptoms (VMS) caused by androgen deficiency in men. Neurokinin-mediated signal transduction may be enhanced during hormone deficiency and may lead to hot flashes. Furthermore, oxanelenthal may inhibit the secretion of multiple hormones, such as testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), by inhibiting NK3R. By inhibiting testosterone production, oxanelenthal may inhibit the proliferation of hormone-sensitive prostate cancer. Drug Indications It may be used to treat schizophrenia, depression, and visceral pain. Mechanism of Action The mechanism of action of oxanelenthal is currently unclear. Multiple preclinical data suggest that activation of the NK3 receptor can enhance the release of biogenic amines, including dopamine and serotonin. NK3 receptor antagonists block the activation of these systems mediated by NK3 receptors.

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Pharmacodynamics
Oxanetainment is a neurokinin-3 (NK3) receptor antagonist. Preliminary clinical trials have shown that oxanetainment is superior to placebo in overall efficacy assessments and positive symptom indicators for schizophrenia.

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Osanetant (SR-142801) is a selective NK3 receptor antagonist developed by Sanofi-Aventis for the treatment of schizophrenia and other CNS disorders. It produces anxiolytic- and antidepressant-like effects and has been studied for potential therapy in schizophrenia, depression, and visceral pain. The compound represents a novel approach to psychiatric disorders by targeting the neurokinin system.

C35H41CL2N3O2

606.63

605.258

160492-56-8

(S)-Osanetant;182621-58-5

219077

White to off-white solid powder

1.25g/cm3

727.9ºC at 760mmHg

394ºC

4.79E-21mmHg at 25°C

1.633

7.293

0

3

8

42

897

1

CC(=O)N(C)C1(CCN(CC1)CCC[C@@]2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5

DZOJBGLFWINFBF-UMSFTDKQSA-N

InChI=1S/C35H41Cl2N3O2/c1-27(41)38(2)35(29-13-7-4-8-14-29)19-23-39(24-20-35)21-9-17-34(30-15-16-31(36)32(37)25-30)18-10-22-40(26-34)33(42)28-11-5-3-6-12-28/h3-8,11-16,25H,9-10,17-24,26H2,1-2H3/t34-/m0/s1

N-[1-[3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl]-4-phenylpiperidin-4-yl]-N-methylacetamide

SR 142801; SR142801; SR-142801

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~66.67 mg/mL (~109.90 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)