Bornaprine

Last updated
Bornaprine
Bornaprine.svg
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral, intravenous, subcutaneous, transdermal
ATC code
Pharmacokinetic data
Elimination half-life 30 hours
Excretion Urine, feces
Identifiers
  • 3-diethylaminopropyl 6-cyclohexylbicyclo[2.2.1]heptane-6-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.205.286 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H31NO2
Molar mass 329.484 g·mol−1
3D model (JSmol)
Density 1.056 g/cm3
Boiling point 434.3 °C (813.7 °F)
  • O=C(OCCCN(CC)CC)C2(c1ccccc1)CC3CCC2C3
  • InChI=1S/C21H31NO2/c1-3-22(4-2)13-8-14-24-20(23)21(18-9-6-5-7-10-18)16-17-11-12-19(21)15-17/h5-7,9-10,17,19H,3-4,8,11-16H2,1-2H3 Yes check.svgY
  • Key:BDNMABJZSXTKAQ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Bornaprine (brand name Sormodrem) is a synthetic anticholinergic medication that is primarily used to treat Parkinson's disease. [1] [2] Additionally, bornaprine has been used to treat other disorders, including hyperhidrosis. [3]

Contents

History

Bornaprine was first synthesized in 1960 by the German scientist H Haas, under the name Kr 399. [4] [5] [6] Additional tests revealed that bornaprine was significantly more effective than nicotine at antagonizing choline. [4] [5] [6] Because of its anticholinergic effects, it was intended to help with the symptoms of Parkinson's. [7] Early clinical trials with Parkinsonian patients (completed in Germany), showed that bornaprine was successful at treating many of the key side-effects of Parkinson's including akinesia, language, tremors, and psychological symptoms. [7]

Pharmacodynamics

Bornaprine Pathway Bornaprine.Pathway.jpg
Bornaprine Pathway

Bornaprine is an antimuscarinic agent that nonselectively antagonizes muscarinic acetylcholine receptors, M1 and M2. [8] Bornaprine has been characterized as a very potent anticholinergic medication and further clinical trials have indicated its effectiveness at treating parkinsonian tremors. [9] [7] [10] [11] Bornaprine also has a pa2 value (affinity of antagonist for receptor) of 7.27 ± 0.21 indicating a high potency. [12]

Pharmacokinetics

Absorption

Bornaprine is successfully absorbed into the plasma of humans within 1–2 hours after an oral dose. [13] Additional oral doses of bornaprine resulted in some accumulation in the plasma. [13]

Excretion

Single oral doses of bornaprine were successfully excreted in urine and feces in rats, dogs, and humans. [13] The following mean excretion rates were also reported during five days for urine and feces: rat 31 and 70%, dog 53 and 39%, and humans 78 and 4%. [13] Excretion was notably prolonged and incomplete at five days in humans, indicating a longer half life and metabolism rate of bornaprine for humans. [13] In human subjects, bornaprine has a half life of approximately 30 hours compared to 5 and 12 hour half lives in rats and dogs, respectively. [13]

Metabolites

Bornaprine is an epimeric mixture of exo and endo esters, and its major metabolites have been identified and include: three isomers of monohydroxy-N-desthel-sormodren, three isomers of monohydroxy-sormodren and 5-hydroxyl. [13] Each of these metabolites were hydroxylated at either C-5 or C-6 in the bicyclic ring. [14] The activity of each of compounds has been studied extensively and 5-hydroxyl showed similar anticholinergic activity to the parent compound when tested in isolated rat atrium unlike other identified metabolites. [12]

Availability

Bornaprine is currently available under the brand name Sormodren in the following countries: Austria (Abbott Pharmaceuticals), Germany (Abbott), Italy (Teofarma Pharmaceuticals), and Turkey (Abbott). Bornaprine is normally administered in a tablet form, however a recent patent is investigating the effect of several anticholinergic drugs, including bornaprine, in transdermal patches. These patches are not currently available to the public market. Bornaprine is not currently on the market in the United States and its clinical trial status is unknown.

Treatment

Parkinson's disease

Like many other anticholinergic drugs, bornaprine had been used to treat the symptoms of Parkinson's disease. Bornaprine most effectively treats the tremors associated with Parkinson's and also helps bradykinesia, hypokinesia, and posture and facial expression. [1]

Hyperhidrosis

Hyperhidrosis occurs in acute phase of spinal cord injured patients and an effective oral treatment for hyperhidrosis has yet to be perfected. [3] A recent study done with patients with medullary lesions found bornaprine to be very effective in decreasing the amount of sweating in patients with minimal side-effects. [3] Bornaprine is now commonly prescribed for treating hyperhidrosis in Europe.

Sleep

When administered to healthy humans, bornaprine suppressed the amount of REM sleep, suggesting that the M1 and M2 receptors are involved in sleep increase and REM latency. [10] This also suggests that bornaprine may be able to be used as a sleep aid in the future. [10]

Side effects

Since bornaprine is a potent anticholinergic drug, it has a similar side effect profile to other anticholinergic drugs, including dry mouth and constipation. [15] [1] Additionally, when bornaprine was administered to patients with secondary parkinsonism, few patients reported transient confusion. [11]

Toxicity

LD50 tests performed on rodents revealed that 26 mg/kg intravenously and 112 mg/kg subcutaneously administered amounts of bornaprine were toxic. [16] Subcutaneous application resulted in ataxia, spastic paralysis, and convulsions. [16]

Synthesis

Bornaprine can be synthesized beginning with atropic acid (2-phenyl acrylic acid, 1). [17] A Diels-Alder reaction with cyclopentadiene (2) gives the bicyclic compound 3. Catalytic hydrogenation over Raney nickel gives 2-phenylbicyclo[2.2.1]heptane-2-carboxylic acid (5). Conversion of the acid to the acid chloride and esterification with 3-diethylaminopropanol (4) completes the synthesis of bornaprine (6).

Synthesis of bornaprine Bornaprine synthesis.svg
Synthesis of bornaprine

Related Research Articles

<span class="mw-page-title-main">Essential tremor</span> Movement disorder that causes involuntary tremors

Essential tremor (ET), also called benign tremor, familial tremor, and idiopathic tremor, is a medical condition characterized by involuntary rhythmic contractions and relaxations of certain muscle groups in one or more body parts of unknown cause. It is typically symmetrical, and affects the arms, hands, or fingers; but sometimes involves the head, vocal cords, or other body parts. Essential tremor is either an action (intention) tremor—it intensifies when one tries to use the affected muscles during voluntary movements such as eating and writing—or it is a postural tremor, which occurs when holding arms outstretched and against gravity. This means that it is distinct from a resting tremor, such as that caused by Parkinson's disease, which is not correlated with movement. Unlike Parkinson's disease, essential tremor may worsen with action.

<span class="mw-page-title-main">Tremor</span> Involuntary muscle contraction

A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the hands. In some people, a tremor is a symptom of another neurological disorder.

<span class="mw-page-title-main">MPTP</span> Chemical compound

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an organic compound. It is classified as a tetrahydropyridine. It is of interest as a precursor to the monoaminergic neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animals.

<span class="mw-page-title-main">Desmethylprodine</span> Opioid analgesic drug

Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. Desmethylprodine has been labeled by the DEA as a Schedule I drug in the United States. It is an analog of pethidine (meperidine) a Schedule II drug. Chemically, it is a reversed ester of pethidine which has about 70% of the potency of morphine. Unlike its derivative prodine, it does not exhibit optical isomerism. It was reported to have 30 times the activity of pethidine and a greater analgesic effect than morphine in rats, and it was demonstrated to cause central nervous system stimulation in mice.

<span class="mw-page-title-main">Glycopyrronium bromide</span> Chemical compound

Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has few to no central effects. It is given by mouth, via intravenous injection, on the skin, and via inhalation. It is a synthetic quaternary ammonium compound. The cation, which is the active moiety, is called glycopyrronium (INN) or glycopyrrolate (USAN).

<span class="mw-page-title-main">Hypokinesia</span> Decreased movement due to basal ganglia dysfunction

Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a symptom of Parkinson's disease shown as muscle rigidity and an inability to produce movement. It is also associated with mental health disorders and prolonged inactivity due to illness, amongst other diseases.

<span class="mw-page-title-main">Chlorprothixene</span> Typical antipsychotic medication

Chlorprothixene, sold under the brand name Truxal among others, is a typical antipsychotic of the thioxanthene group.

<span class="mw-page-title-main">Sulpiride</span> Atypical antipsychotic

Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic medication of the benzamide class which is used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and is sometimes used in low dosage to treat anxiety and mild depression.

<span class="mw-page-title-main">Biperiden</span> Group of stereoisomers

Biperiden, sold under the brand name Akineton among others, is a medication used to treat Parkinson disease, certain drug-induced movement disorders and Tourette Syndrome. It is not recommended for tardive dyskinesias. It is taken by mouth, injection into a vein, or muscle.

<span class="mw-page-title-main">Trihexyphenidyl</span> Antispasmodic drug

Trihexyphenidyl is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.

<span class="mw-page-title-main">Oxybutynin</span> Medication for overactive bladder

Oxybutynin, sold under the brand name Ditropan among others, is an anticholinergic medication primarily used to treat overactive bladder. It is widely considered a first-line therapy for overactive bladder due to its well-studied side effect profile, broad applicability, and continued efficacy over long periods of time. It works similar to tolterodine, darifenacin, and solifenacin, although it is usually preferred over these medications. It is sometimes used off-label for treatment of hyperhidrosis, or excessive sweating. It has also been used off-label to treat bedwetting in children, but this use has declined, as it is most likely ineffective in this role. It is taken by mouth or applied to the skin.

<span class="mw-page-title-main">Sodium phenylbutyrate</span> Chemical compound

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

<span class="mw-page-title-main">Procyclidine</span> Group of stereoisomers

Procyclidine is an anticholinergic drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia, Parkinson's disease, and idiopathic or secondary dystonia.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

<span class="mw-page-title-main">Budipine</span> Pharmaceutical drug

Budipine is an antiparkinson agent marketed for the treatment of Parkinson's disease.

<span class="mw-page-title-main">Mazaticol</span> Chemical compound

Mazaticol (Pentona) is an anticholinergic used as an antiparkinsonian agent in Japan.

<span class="mw-page-title-main">Housane</span> Chemical compound

Housane or bicyclo[2.1.0]pentane is a saturated cycloalkane with the formula C5H8. It is a colorless, volatile liquid at room temperature. It was named "housane" because of its shape, which resembles a simple drawing of a house. Structurally, the molecule consists of cyclopropane fused to cyclobutane. The synthesis of molecules containing multiple strained rings, such as housane, is a traditional endeavor in synthetic organic chemistry.

<span class="mw-page-title-main">Befiradol</span> Chemical compound

Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.

EXP-561 is an investigational drug that acts as an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. It was developed in the 1960s by Du Pont and was suggested as a potential antidepressant but failed in trials and was never marketed.

Prodipine is an experimental antiparkinsonian agent of the 4,4-diphenylpiperidine series related to budipine which was never marketed. It was the predecessor of budipine and was similarly found to be effective in the treatment of Parkinson's disease. However, prodipine produced side effects including gastrointestinal adverse effects, nausea and vomiting, and hypotension. Due to the nausea and vomiting with the oral form, it could only be tolerated with intravenous administration. As a result, budipine, which had fewer side effects, was developed instead.

References

  1. 1 2 3 Cantello R, Riccio A, Gilli M, Delsedime M, Scarzella L, Aguggia M, Bergamasco B (February 1986). "Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients". Italian Journal of Neurological Sciences. 7 (1): 139–43. doi:10.1007/BF02230432. PMID   3514543.
  2. Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-181-4.
  3. 1 2 3 Sergi R, Massone A, Moretto S, Oggerino C, Bertolotto F, Losio L, Ottonello M (August 2008). "Hyperhidrosis treatment with bornaprine in the acute phase of spinal cord-injured patients". Spinal Cord. 46 (8): 571–3. doi: 10.1038/sc.2008.12 . PMID   18332889.
  4. 1 2 Haas H (1960). "3-Piperidino-1-phenyl-1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-propanol (Akineton). II". Archives Internationales de Pharmacodynamie (in German). 78: 204–38.
  5. 1 2 Haas H, Wulzinger H (1960). "3-Piperidino-1-phenyl-1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-propanol (Akineton). III". Archives Internationales de Pharmacodynamie Therapy (in German). 78: 239–52.
  6. 1 2 Haas H (1964). "Supplementary investigations of the spasmolytic bicyclophenamine (β-pyrrolidinylethyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate)". Arzneimittel-Forschung (in German). 14: 342–7.
  7. 1 2 3 Avenarius HJ, Gesterbrandt F (1968). "Kr 339, ein neus tremorhemmendes Praparat zu Behandlung des Parkinson Syndromes". Wien klin Wochenschr (in German) (80th ed.).
  8. Kreiskott H, Kretzschmar R (1985). "Neuere pharmakologische Aspekte zu den zentralen Anticholinergika Biperiden und Bornaprin". Das Parkinson-Syndrom (in German). pp. 277–87.
  9. Ascher PW (October 1976). "[Anticholinergic treatment of Parkinson's disease (author's transl)]". Wiener Klinische Wochenschrift. 88 (19): 641–6. PMID   790774.
  10. 1 2 3 Hohagen F, Lis S, Riemann D, Krieger S, Meyer C, Montero RF, et al. (August 1994). "Influence of biperiden and bornaprine on sleep in healthy subjects". Neuropsychopharmacology. 11 (1): 29–32. doi: 10.1038/npp.1994.33 . PMID   7945741.
  11. 1 2 Sancesario G, Cicardi MC, Fiermonte G, Giacomini P, Stanzione P (September 1984). "Effectiveness of bornaprine on parkinsonian tremor". Italian Journal of Neurological Sciences. 5 (3): 289–93. doi:10.1007/bf02043960. PMID   6500902.
  12. 1 2 Hufford CD, Elmarakby SA, Walker LA (1991). "Anticholinergic activity of bornaprine and its metabolites in the isolated rat atrium". Pharmacology. 42 (1): 23–7. doi:10.1159/000138764. PMID   2057518.
  13. 1 2 3 4 5 6 7 Mayo BC, Biggs SR, Chasseaud LF, Hawkins DR, Darragh A, O'Kelly DA (December 1980). "The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 10 (12): 873–88. doi:10.3109/00498258009033821. PMID   7210700.
  14. Elmarakby SA, Clark AM, Baker JK, Hufford CD (June 1986). "Microbial metabolism of bornaprine, 3-(diethylamino)propyl 2-phenylbicyclo[2.2.1]heptane-2-carboxylate". Journal of Pharmaceutical Sciences. 75 (6): 614–8. doi:10.1002/jps.2600750620. PMID   3735109.
  15. Bergamasco B, Cantello R, Delsedime M, Gilli M, Riccio A, Aguggia M (October 1985). "[Preliminary open multicenter study on the anti-tremorigenic effectiveness of bornaprine (Sormodren)]". Minerva Medica. 76 (40): 1877–81. PMID   4058785.
  16. 1 2 "Bornaprine". United States National Library of Medicine. National Institute of Health. Retrieved 1 March 2014.
  17. DE1044809, Kraft Helmut, Klavehn Wilfrid, U.S. patent 3,083,204 (1963 to Knoll Ag).