Orphenadrine ((±)-Orphenadrine) is a skeletal muscle relaxant and NMDA antagonist, and also has anti-Parkinson's disease, antihistamine, antitremor, antispasmodic and analgesic effects. Orphenadrine can inhibit the binding of [3H]MK-801 to the phencyclidine (PCP) binding site of the NMDA receptor. Orphenadrine is also an anticholinergic agent and cytochrome P450 (CYP) 2B inducer. Orphenadrine may play a pro-tumor role, causing CAR nuclear translocation, leading to the generation of microsomal reactive oxygen species (ROS) and oxidative stress. Orphenadrine also plays a neuroprotective role, protecting rat cerebellar granule cells (CGC) from 3-NPA-induced death, and has inhibitory potential for neurodegenerative diseases mediated by excessive activation of NMDA receptors.

Physicochemical Properties

Molecular Formula	C18H23NO
Molecular Weight	269.38
CAS #	83-98-7
Related CAS #	Orphenadrine citrate;4682-36-4;Orphenadrine hydrochloride
PubChem CID	4601
Appearance	Light yellow to brown <25°C solid powder,>25°C liquid
Density	1.0278 (rough estimate)
Boiling Point	195ºC at 12 ATM
Melting Point	25°C
Index of Refraction	1.5740 (estimate)
LogP	3.663
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	6
Heavy Atom Count	20
Complexity	260
Defined Atom Stereocenter Count	0
SMILES	CC1=CC=CC=C1C(C2=CC=CC=C2)OCCN(C)C
Synonyms	(±)-Orphenadrine
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	NMDA receptor[1]; CYP450 2B[2]; Cholinesterase (ChE)[3]
ln Vitro	Orphenadrine (30-300 μM) exhibits relatively fast concentration-dependent open channel blockade kinetics with a Koff of 0.013[1].
ln Vivo	In a study of the tumor-promoting effects of orphenadrine, male rats were pretreated with a single intraperitoneal injection of N-diethylnitrosamine (DEN) for 2 weeks. Orphenadrine (0, 750, 1500 ppm; po; 6 wk) accelerated hepatocyte proliferation and induced liver tumor-promoting activity[2]. Orphenadrine (30 mg/kg; po; 3 d) protected rats from the effects of 3-nitropropionic acid (3-NPA) (30 mg/kg; 3 d), which resulted in increased expression of neuronal damage markers [(3)H]-PK 11195 and HSP27 in astrocytes[3].
Cell Assay	Cell Viability Assay[1] Cell Types: NMDA open-channel Tested Tested Concentrations: 30, 100 and 300 μM Incubation Duration: 5 seconds; with 200 μM NMDA Experimental Results: Nearly completely inhibited [3H]MK-801 binding at 100 μM. Exhibited relatively fast, Tested Tested Concentrations-dependent open channel blocking kinetics.
Animal Protocol	Animal/Disease Models: Liver tumor model in male rats pre-treated by N-diethylnitrosamine[2] Doses: 0, 750, 1500 ppm Route of Administration: PO; for 6 weeks Experimental Results: Increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1. Increased microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine.
References	[1]. Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Transm Gen Sect. 1995;102(3):237-46. [2]. Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress. J Toxicol Sci. 2013;38(3):403-13. [3]. Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitro and in vivo. Br J Pharmacol. 2001 Feb;132(3):693-702.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~371.22 mM; with ultrasonication)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.28 mM)(saturation unknown) in 10% DMSO 40% PEG300 5% Tween-80 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 and add it to 400 μL PEG300, mix well; then add 50 μL Tween-80 to the above system, mix well; then continue to add 450 μL of normal saline to make up to 1 mL. Preparation of normal saline: Dissolve 0.9 g of sodium chloride in ddH₂O and make up to 100 mL to obtain a clear and transparent normal saline solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.28 mM)(saturation unknown) in 10% DMSO 90% (20% SBE-β-CD in 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 and add it to 900 μL of 20% SBE-β-CD saline solution and mix well. 2 g SBE-β-CD (sulfobutyl ether β-cyclodextrin) powder is diluted to 10 mL of saline and completely dissolved until clear and transparent. Solubility in Formulation 3: ≥ 2.5 mg/mL (9.28 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 and add it to 900 μL corn oil and mix well.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.7122 mL	18.5611 mL	37.1223 mL
	5 mM	0.7424 mL	3.7122 mL	7.4245 mL
	10 mM	0.3712 mL	1.8561 mL	3.7122 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.