TCS 1102 is a potent, non-selective dual orexin receptor antagonist with Ki values of 0.2 and 3 nM for OX2 and OX1 receptors respectively. In rats exposed to footshock for 14 days, TCS-1102 (10 and 20 mg/kg, i.p.) was found to reduce fear and anxiety. Moreover, anxiolytic effects specific to HR were observed with TCS-1102 (10 mg/kg, i.p.) when tested in the elevated T-maze. This work shows that rats exposed to a single footshock episode develop anxiety, which is associated with the orexin system. Moreover, it offers preclinical evidence in favor of orexin antagonist therapy for anxiety brought on by a sudden stressful event.

Physicochemical Properties

Molecular Formula	C27H26N4O2S
Molecular Weight	470.59
Exact Mass	470.178
Elemental Analysis	C, 68.91; H, 5.57; N, 11.91; O, 6.80; S, 6.81
CAS #	916141-36-1
Related CAS #	916141-36-1
PubChem CID	11960895
Appearance	White to off-white solid powder
LogP	5.549
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	6
Heavy Atom Count	34
Complexity	715
Defined Atom Stereocenter Count	1
SMILES	CN1C(SCC(N2CCC[C@H]2C(=O)NC2=CC=CC=C2C2C=CC=CC=2)=O)=NC2C=CC=CC1=2
InChi Key	YSBGRVXJEMSEQY-DEOSSOPVSA-N
InChi Code	InChI=1S/C27H26N4O2S/c1-30-23-15-8-7-14-22(23)29-27(30)34-18-25(32)31-17-9-16-24(31)26(33)28-21-13-6-5-12-20(21)19-10-3-2-4-11-19/h2-8,10-15,24H,9,16-18H2,1H3,(H,28,33)/t24-/m0/s1
Chemical Name	(2S)-1-[2-(1-methylbenzimidazol-2-yl)sulfanylacetyl]-N-(2-phenylphenyl)pyrrolidine-2-carboxamide
Synonyms	TCS 1102; TCS1102; TCS-1102
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	OX1 ( Ki = 3 nM ); OX2 ( Ki = 0.2 nM )
ln Vitro	TCS 1102 (10 μM) suppresses the Ca2+ responses of CHO-hOX2 cells to Orexin A (human, rat, mouse) (HY-106224) and Yan 7874 (an agonist of the Orexin receptor)[2].
ln Vivo	TCS 1102 (compound 18) (15, 50, 100 mg/kg; i.p; single dose) inhibits rat locomotion in a dose-dependent manner[1]. TCS-1102 (10 and 20 mg/kg; i.p.; single dose) reduces rats' anxiety and fear following footshock exposure. Moreover, when tested in the elevated T-maze, TCS-1102 (10 mg/kg; i.p.; single dose) demonstrates anxiolytic effects for high responders (HR) rats[3].
Enzyme Assay	TCS 1102 is a potent, non-selective antagonist of the dual orexin receptor, with Ki values for the OX2 and OX1 receptors of 0.2 and 3 nM, respectively.
Animal Protocol	Male Sprague–Dawley rats (130-160 g) Dosage: 10 and 20 mg/kg Administration: Intraperitoneal injection; 30 min before received the footshocks
References	[1]. Proline bis-amides as potent dual orexin receptor antagonists. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1425-30. [2]. Orexin receptor agonist Yan 7874 is a weak agonist of orexin/hypocretin receptors and shows orexin receptor-independent cytotoxicity. PLoS One. 2017 Jun 2;12(6):e0178526. [3]. Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct. 2013 Aug 18.

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 100 mg/mL (~212.5 mM) Water: <1 mg/mL Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.31 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.31 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1250 mL	10.6250 mL	21.2499 mL
	5 mM	0.4250 mL	2.1250 mL	4.2500 mL
	10 mM	0.2125 mL	1.0625 mL	2.1250 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.