NMDA receptor[1]; CYP450 2B[2]; Cholinesterase (ChE)[3]
NMDA receptor (antagonist), muscarinic acetylcholine receptors (antagonist), histamine H1 receptors (inhibitor), CYP450 2B (inducer)

Orphenadrine (30-300 μM) exhibits relatively fast concentration-dependent open channel blockade kinetics with a Koff of 0.013[1].

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In vitro, Orphenadrine (30-300 microM) demonstrates concentration-dependent open-channel blocking kinetics at the NMDA receptor with a Koff of 0.013. It inhibits the binding of [3H]MK-801 to the PCP binding site of the NMDA receptor. Orphenadrine also exhibits neuroprotection, protecting rat cerebellar granule cells (CGC) from 3-NPA-induced death.

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].

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Orphenadrine (30 mg/kg; oral; 3 days) prevents 3-nitropropionic acid (3-NPA)-induced neurotoxicity in rats. It reduces the 3-NPA-induced increase in neuronal damage markers [(3H]-PK11195 and HSP27) in astrocytes. At higher doses (750-1500 ppm in diet; 6 weeks) it accelerates hepatocyte proliferation and induces liver tumor-promoting activity in DEN-pretreated rats.

Standard radioligand binding assays using [3H]MK-801 to label the PCP site of the NMDA receptor in rat brain membrane homogenates; incubation with varying concentrations of Orphenadrine; filtration through GF/B filters; scintillation counting; IC50 determination by non-linear regression.

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.

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Cell culture: Rat cerebellar granule neurons cultured in BME medium; incubation with test compound and 3-NPA; cell viability assessment by MTT or LDH release; Hoechst 33342 staining for nuclear morphology; propidium iodide uptake for membrane integrity.

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.

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Rat model: Single IP injection of DEN (200 mg/kg) for initiation; 2 weeks recovery; then Orphenadrine (0, 750, 1500 ppm) in diet for 6 weeks; sacrifice; liver weight, GST-P positive foci analysis by immunohistochemistry; PCNA staining for proliferation index.

Absorption, Distribution and Excretion
Offenarin is almost completely absorbed by the gastrointestinal tract. The bioavailability of H-3-offenarin citrate in human tissues appears to be comparable between capsule and tablet forms. The amount of (3)H excreted in urine is six times that in feces, and the excretion rate is relatively slow, likely due to the slow release of (3)H in tissues or via enterohepatic circulation. The elimination half-life (T2) of offenarin citrate and its major metabolite is between 14 and 25 hours. /Citrate/ A considerable amount of biliary excretion of offenarin has been observed in rats… Detailed studies have been conducted on the (14)C- or (3)H-biliary excretion of offenarin. The amount of radioactive material excreted in bile after intravenous injection is three times greater than after oral administration. The concentration of radioactive material in the liver is one hundred times that in the blood, and the concentration in bile is seven times that in the liver. /Citrate/

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Metabolism / Metabolites
Biotransformation primarily occurs in the liver. The pharmacologically active metabolites are N-demethylolphenadrine and N,N-didemethylolphenadrine. Unlike diphenhydramine, olphenadrine is a potent anti-Parkinson's disease drug; the difference in pharmacological activity may be attributed to the different metabolic pathways of the two drugs and the correspondingly reduced metabolic and excretion rates of olphenadrine. Biotransformation of the diphenhydramine analog olphenadrine in rats…is achieved via oxidative dealkylation to produce secondary and primary amines…corresponding to olphenadrine and its O-dealkylation product, 2-methylbenzyl alcohol. Human studies revealed eight excretion products. In addition to the secondary amine (8.1% of dose) and the primary amine (4.4%), 2-methylbenzyl alcohol (0.5%), olphenadrine N-oxide (4.6%), glucuronide (13.0%), and 2-methylphenylhydroxyacetic acid (0.2%) have been identified. Since the o-tolylphenylmethyl residue is excreted unchanged in the urine, accounting for 50% of the dose, the metabolism involving the aromatic ring is also the main metabolic pathway of olphenadrine. Products corresponding to the properties of 2-carboxydiphenylhydramine and its glutamine conjugate have been detected in rat bile secretion. For more complete data on the metabolism/metabolites of olphenadrine (6 metabolites in total), please visit the HSDB record page. Biotransformation mainly occurs in the liver. The pharmacologically active metabolites are N-demethylolphenadrine and N,N-didemethylolphenadrine. Half-life: 13-20 hours.

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Biological Half-Life
13-20 hours

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Orphenadrine's clinical PK: oral absorption rapid (Tmax ~1.5-2 h); plasma protein binding ~95%; extensively metabolized by CYP450 (primarily CYP2B6 and CYP3A4); elimination half-life 13-20 h; renal excretion of metabolites; steady-state reached within 3-5 days with chronic dosing.

Toxicity Summary
Ophenazine can bind to and inhibit histamine H1 receptors and NMDA receptors. It can restore motor dysfunction induced by nerve blocks, especially hyperactivity. Striatal dopamine deficiency enhances the excitatory effect of the cholinergic system. Ophenazine's anticholinergic effect can counteract this excitatory effect. It may have a relaxing effect on skeletal muscle spasms and may also have a mood-enhancing effect.

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Hepatotoxicity
Although oxyphenadrine has been used clinically for a long time, there is no evidence of its hepatotoxicity. Several cases of oxyphenadrine overdose leading to severe cardiopulmonary arrest and ischemic liver injury have been reported. Regular doses of oxyphenadrine do not appear to cause liver damage. Probability Score: E (Unlikely to be a clinically obvious cause of liver injury). Drug Category: Muscle Relaxant

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no publicly available information regarding the use of oxyphenadrine during lactation. The manufacturer estimates that the drug concentration in breast milk may be low. The anticholinergic activity of this drug may interfere with milk production. Alternative medications are recommended.
◉ Effects on Breastfed Infants
As of the revision date, no relevant publicly available information was found.
◉ Effects on Lactation and Breast Milk
Ophenadrine has anticholinergic activity. Anticholinergic drugs can inhibit lactation in animals, possibly by inhibiting the secretion of growth hormone and oxytocin. Anticholinergic drugs can also lower serum prolactin levels in non-lactating women. Prolactin levels in established lactating mothers may not affect their ability to breastfeed.

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Protein Binding
95%

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Interactions
It has been reported that when oxyphenalin is used concurrently with propoxyphene, oxyphenalin enhances the central nervous system effects of propoxyphene. In mice, neostigmine and physostigmine both increase the toxicity of oxyphenalin. However, arecoline… provides significant protection against acute lethal effects.

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Toxicity Data
LD50: 100 mg/kg (oral, mouse) (A308)
LD50: 255 mg/kg (oral, rat) (A308)

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Human side effects: dry mouth, dizziness, sedation, constipation, urinary retention, tachycardia, blurred vision (anticholinergic effects). Rare hepatotoxicity reported. Rat studies: proliferative effects on liver at high doses; promotes oxidative stress via CAR activation and ROS production. Mouse LD50 oral ~350 mg/kg.

[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.

Orphenadrine is a tertiary amine compound, a phenyl-o-tolyl methyl ether of 2-(dimethylamino)ethanol. It possesses various pharmacological effects, including H1 receptor antagonist, anti-Parkinson's disease drug, muscarinic receptor antagonist, parasympathetic nerve blocker, muscle relaxant, NMDA receptor antagonist, and anti-movement disorder drug. It is an ether-type tertiary amine compound. As a muscarinic receptor antagonist, it is used to treat drug-induced Parkinson's syndrome and relieve pain caused by muscle spasms. Orphenadrine is a muscle relaxant. Its physiological action is achieved through centrally mediated muscle relaxation. Orphenadrine is a centrally acting muscle relaxant that has been used clinically for over 50 years without being associated with liver damage or clinically significant drug-induced liver disease. Orphenadrine is a muscarinic receptor antagonist with muscle relaxant effects. Although its mechanism of action is not fully understood, ophenazo appears to block muscarinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors in the central nervous system (CNS). This may interfere with the transmission of nerve impulses from the spinal cord to the muscles, thus aiding in muscle relaxation. Furthermore, ophenazo also antagonizes histamine H1 receptors. Oophenazo has only been found in individuals who have taken the drug. It is a muscarinic receptor antagonist used to treat drug-induced Parkinson's syndrome and relieve pain caused by muscle spasms. [PubChem] Oophenazo binds to and inhibits histamine H1 and NMDA receptors. It can restore motor dysfunction induced by nerve blockers, particularly hyperexcitability. Striatal dopamine deficiency enhances the excitatory activity of the cholinergic system. This excitatory activity can be counteracted by the anticholinergic effect of ophenazo. It may have a relaxing effect on skeletal muscle spasms and may have a mood-enhancing effect.
A muscarinic receptor antagonist used to treat drug-induced Parkinson's syndrome and relieve pain caused by muscle spasms.
See also: Ipratropium bromide (related drug); Ophenadrine citrate (active ingredient); Tolterodine tartrate (related drug)...See more...

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Drug Indication
Suitable for use as an adjunct to rest, physical therapy, and other measures to relieve acute pain associated with musculoskeletal disorders.
FDA label

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Mechanism of Action
Disipal binds to and inhibits histamine H1 receptors and NMDA receptors. It can restore motor dysfunction induced by nerve blockers, especially hyperkinesis. Striatal dopamine deficiency enhances the excitatory effect of the cholinergic system. Disipal's anticholinergic effect counteracts this excitatory effect. It may have a relaxing effect on skeletal muscle spasms and a mood-enhancing effect. Anti-Parkinson's drugs can also block cholinergic receptors. These are…Disipal…which blocks the release of acetylcholine from parasympathetic nerve endings. …It reduces voluntary muscle spasms through central anticholinergic action, similar to atropine in this respect. /Citrate/ Except at near-lethal doses, nerve conduction, neuromuscular transmission, and muscle excitability are not inhibited. Its significant effect is preferential inhibition of spinal polysynaptic reflexes rather than monosynaptic reflexes. /Central muscle relaxant/

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Therapeutic Uses
Anti-Parkinson's disease drugs; muscarinic receptor antagonists; central muscle relaxants; parasympathetic nerve blockers
Anthistamines can reduce voluntary muscle spasms…used for the symptomatic treatment of Parkinson's disease. In addition to reducing spasms, palpebral fissures, and blepharospasm, it can also reduce drooling and sweating. …Also used to treat acute skeletal muscle spastic disorders…/Citrates/
All types of abnormal muscle tone and hyperreflexia, such as those caused by decerebrate or spinal cord or supraspinous lesions, can be reduced with non-paralyzing doses…They can also prevent certain convulsive agents, especially strychnine, and seizures caused by electroconvulsive therapy. /Central muscle relaxants/
…Intravenous administration has proven effective in treating acute muscle spasms associated with trauma and inflammation. They also help with muscle relaxation during certain orthopedic manipulations. …May temporarily relieve some symptoms of cerebral palsy…/Central muscle relaxants/
For more (complete) data on the therapeutic uses of ophenazoline (7 types), please visit the HSDB record page.

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Drug Warnings
Tremors may worsen. Therefore, this medication should only be used as an adjunct to other therapies. /Citrate/
...Contraindicated in patients with acute angle-closure glaucoma or myasthenia gravis. Use with caution in patients with gastrointestinal obstruction, urinary retention, urinary tract obstruction, or tachycardia. /Citrate/

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Pharmacodynamics
Offenafil is used in conjunction with rest, physical therapy, and other measures to relieve discomfort caused by acute painful musculoskeletal disorders. Offenafil is an anticholinergic drug that primarily acts on the central nervous system, with weaker peripheral effects. It also has mild antihistamine and local anesthetic effects. Parkinson's syndrome is caused by a decrease in dopamine, leading to an imbalance in cholinergic and dopaminergic neurotransmission in the basal ganglia. Offenafil can restore this physiological balance and has significant efficacy in treating rigidity and tremor symptoms of Parkinson's disease and Parkinson's syndrome. Its efficacy is slightly weaker for bradykinesia.

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Orphenadrine is an FDA-approved drug marketed under brand names including Norflex, Disipal, and Brocasipal. It is indicated for the relief of acute painful musculoskeletal conditions as an adjunct to rest, physical therapy, and other measures. First synthesized in the late 1940s, it has a long clinical history.

C18H23NO

269.38

269.178

83-98-7

Orphenadrine citrate;4682-36-4;Orphenadrine hydrochloride

4601

Light yellow to brown <25°C solid powder,>25°C liquid

1.0278 (rough estimate)

195ºC at 12 ATM

< 25 °C ; CRYSTALS; MP: 156-157 °C; PH OF AQ SOLN ABOUT 5.5 /HYDROCHLORIDE/ ; 156 - 157 °C

1.5740 (estimate)

3.663

0

2

6

20

260

0

CC1=CC=CC=C1C(C2=CC=CC=C2)OCCN(C)C

QVYRGXJJSLMXQH-UHFFFAOYSA-N

InChI=1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3

N,N-dimethyl-2-[(2-methylphenyl)-phenylmethoxy]ethanamine

(±)-Orphenadrine

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

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.

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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.

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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.

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