Deramciclane

Last updated
Deramciclane
Deramciclane.svg
Clinical data
Other namesDeramciclane
ATC code
  • none
Identifiers
  • N,N-dimethyl-2-([(1R,4R,6S)-1,7,7-trimethyl-6-phenyl-6-bicyclo[2.2.1]heptanyl]oxy)ethanamine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H31NO
Molar mass 301.474 g·mol−1
3D model (JSmol)
  • C[C@@]12CC[C@@H](C1(C)C)C[C@]2(CCCN(C)C)c3ccccc3
  • InChI=1S/C21H33N/c1-19(2)18-12-14-20(19,3)21(16-18,13-9-15-22(4)5)17-10-7-6-8-11-17/h6-8,10-11,18H,9,12-16H2,1-5H3/t18-,20-,21-/m1/s1 X mark.svgN
  • Key:NTGJQFUKCCRUPP-HMXCVIKNSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. [1] Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, [2] as an inverse agonist at the 5-HT2C receptor, [3] and as a GABA reuptake inhibitor. [4] The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. [5] Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, [6] but it is a weak inhibitor of CYP2D6. [7] Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. [8] Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects. [9] [10]

Contents

Commercial history

Deramciclane was discovered by EGIS Pharmaceuticals Ltd in Budapest, Hungary. In 2000, EGIS signed over exclusive rights to Orion Pharma to further develop, register, and market deramciclane. Successful pre-clinical, Phase I, and Phase II trials looked promising to the company and its investors even up until the third quarter of 2002. [11] Phase I studies show little to no side effects of deramciclane. [8] [12] [13] [14] Phase II studies show little to no side effects and statistically significant improvement on the Hamilton Anxiety Rating Scale in response to daily 60 mg doses, but not in response to daily 10 or 30 mg doses. [10] Finally, in February, 2003, deramciclane development for use against general anxiety disorder (GAD) was discontinued during Phase III trials due to clinically insignificant results compared to placebo groups. [11]

Pharmacokinetics

There have been several clinical studies to examine the pharmacokinetics of deramciclane, which can readily cross the blood–brain barrier. [2] [15] Overall, studies show that deramciclane follows linear pharmacokinetics in humans with oral daily doses ranging from 3–150 mg and twice daily doses ranging from 10–60 mg. [8] Additionally, no differences have been found in adsorption, distribution, metabolism, or elimination when an oral dose is administered in tablet or capsule form. [13]

Deramciclane is rapidly absorbed from the gastrointestinal tract. Studies show that the drug can be detected in plasma as quickly as 20 minutes after dosing. [13] Deramciclane demonstrates a Tmax of 2–4 hours and is unaffected by dosage. [8] [14] The Cmax at this time is approximately 140 ng/mL. [8] A typical PTF (peak trough fluctuation) is 70-80% over four weeks of administration, and is unaffected by dose. [8] [14] The oral tablet of deramciclane yields a bioavailability of 36% on average, [8] which is considered decent enough for oral administration and avoid the necessity of a more invasive route. [16]

The pharmacokinetics of deramciclane are also studied in rats, mice, rabbits, and dogs. Rat and rabbits show the fastest metabolism rates of the drug, and dogs are the only animals to show non-linear pharmacokinetics of deramciclane. [9] Phase I metabolism in rat hepatocytes is similar enough to that in humans that the rat can be used as a predictive model for human metabolism of deramciclane. [9] In rats, the Tmax is found to be 0.5 hours after a single 10 mg/kg dose and the half-life of deramciclane is about 3.5-5.5 hours. [17] As expected, deramciclane reaches greatest peak plasma concentrations with intravenous administration, followed by intraperitoneal, then oral administration with the lowest peak plasma concentration. [17]

Studies assessing the elimination half-life of deramciclane point to a range of 20–32 hours for T1/2. [13] [18] The elimination half-life appears to increase with dosage. [14] There is some evidence for accumulation of deramciclane, though it is a topic of debate. [8] [14]

Metabolism

It is important to understand the metabolism pathway of a drug to better understand its pharmacology, toxicity, and animal model predictability. The metabolism pathway in humans is not entirely clear, though certain reactions have been shown to happen in the breakdown of deramciclane. For example, deramciclane undergoes side chain modification and oxidation at multiple positions on the molecule. [9] The side chain reaction forms phenylborneol and N-desmethyl deramciclane which is the active metabolite of deramciclane. [9] Oxidation of the molecule results in many hydroxy-, carboxy-, and N-oxide derivatives. [9]

Food interaction

Also important to the pharmacokinetics of a drug is its interactions with food during adsorption because this affects the dosage required. Deramciclane is an acid-labile compound. Acid-labile compounds are more easily broken down in acidic environments, so the decrease in stomach pH as a result of the presence of food could have adverse effects on the bioavailability of deramciclane. Clinical studies investigating the effects of food or lack thereof on deramciclane adsorption show that there is a statistically significant, but not clinically relevant, increase in bioavailability of deramciclane when administered with food because the point of critical instability of deramciclane is relatively low at a pH of 2. The presence of food does not affect deramciclane's elimination half-life (T1/2) or mean residence time (MRT). [12]

Safety and side effects

All clinical studies have shown that deramciclane is well tolerated in humans at dosages ranging between 0.2–150 mg. [13] All reported side effects were mild-moderate with the most common side effect being headache and dizziness. No severe side effects were reported in any clinical trial, and no side effects were found to be dose-dependent. [13] Trial participants showed no significant increases in liver enzyme activity [8] and no changes in ECGs, [8] systolic blood pressure, diastolic blood pressure, HDL cholesterol, or LDL cholesterol levels. [14] Another advantage to deramciclane is that it did not produce any withdrawal effects after long-term studies, like other anxiolytics do.

See also

Related Research Articles

<span class="mw-page-title-main">Fluvoxamine</span> SSRI antidepressant drug

Fluvoxamine, commonly sold under the brand names Luvox and Faverin, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder (OCD), but is also used to treat anxiety disorders such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.

<span class="mw-page-title-main">Hydroxyzine</span> Antihistamine drug

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, insomnia, anxiety, and nausea, including that due to motion sickness. It is used either by mouth or injection into a muscle.

<span class="mw-page-title-main">Buspirone</span> Medication used to treat anxiety disorders


Buspirone, sold under the brand name Buspar, among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. It is a serotonin 5-HT1A receptor agonist, increasing action at serotonin receptors in the brain. It is taken orally, and takes two to six weeks to be fully effective.

<span class="mw-page-title-main">Cetirizine</span> Antihistamine medication

Cetirizine is a second-generation antihistamine used to treat allergic rhinitis, dermatitis, and urticaria (hives). It is taken by mouth. Effects generally begin within thirty minutes and last for about a day. The degree of benefit is similar to other antihistamines such as diphenhydramine, which is a first-generation antihistamine.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do.

<span class="mw-page-title-main">Doxepin</span> Medication to treat depressive disorder, anxiety disorders, chronic hives, and trouble sleeping

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

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

Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.

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

Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.

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

Clotiazepam is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring. It possesses anxiolytic, skeletal muscle relaxant, anticonvulsant, sedative properties. Stage 2 NREM sleep is significantly increased by clotiazepam.

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

Tofisopam is an anxiolytic that is marketed in several European countries. Chemically, it is a 2,3-benzodiazepine. Unlike other anxiolytic benzodiazepines however, tofisopam does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines and muscimol, but not sodium valproate, carbamazepine, phenobarbital, or phenytoin. Tofisopam is indicated for the treatment of anxiety and alcohol withdrawal, and is prescribed in a dosage of 50–300 mg per day divided into three doses. Peak plasma levels are attained two hours after an oral dose. Tofisopam is not reported as causing dependence to the same extent as other benzodiazepines, but is still recommended to be prescribed for a maximum of 12 weeks.

<span class="mw-page-title-main">Delorazepam</span> Benzodiazepine medication

Delorazepam, also known as chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam. It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.

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

Benzoctamine is a drug that possesses sedative and anxiolytic properties. Marketed as Tacitin by Ciba-Geigy, it is different from most sedative drugs because in most clinical trials it does not produce respiratory depression, but actually stimulates the respiratory system. As a result, when compared to other sedative and anxiolytic drugs such as benzodiazepines like diazepam, it is a safer form of tranquilizing. However, when co-administered with other drugs that cause respiratory depression, like morphine, it can cause increased respiratory depression.

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

Metaclazepam is a drug which is a benzodiazepine derivative. It is a relatively selective anxiolytic with less sedative or muscle relaxant properties than other benzodiazepines such as diazepam or bromazepam. It has an active metabolite N-desmethylmetaclazepam, which is the main metabolite of metaclazepam. There is no significant difference in metabolism between younger and older individuals.

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

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

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

Premazepam is a Pyrrolodiazepine class of drug. It is a partial agonist of benzodiazepine receptors and was shown in 1984 to possess both anxiolytic and sedative properties in humans but was never marketed.

<span class="mw-page-title-main">TPA-023</span> Chemical compound

TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a mixed, subtype-selective ligand of the benzodiazepine site of α1, α2, α3, and α5-containing GABAA receptors, where it acts as a partial agonist at benzodiazepine sites of the α2 and α3-containing subtypes, but as a silent antagonist at α1 and α5-containing subtypes. It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.

<span class="mw-page-title-main">Enobosarm</span> Investigational selective androgen receptor modulator

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.

<span class="mw-page-title-main">Pomaglumetad</span> Drug, used as a treatment for schizophrenia

Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.

<span class="mw-page-title-main">Bilastine</span> Antihistamine medication

Bilastine is an antihistamine medication used to treat hives (urticaria), allergic rhinitis and itchy inflamed eyes (allergic conjunctivitis) caused by an allergy. It is a second-generation antihistamine and takes effect by selectively inhibiting the histamine H1 receptor, preventing these allergic reactions. Bilastine has an effectiveness similar to cetirizine, fexofenadine, and desloratadine.

References

  1. Orion Pharma Inlicenses Deramciclane from Egis Pharmaceuticals. Phase 3 Program in Anxiety has Started, 2000 http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=29979
  2. 1 2 Kanerva H, Vilkman H, Någren K, Kilkku O, Kuoppamäki M, Syvälahti E, Hietala J (July 1999). "Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study". Psychopharmacology. 145 (1): 76–81. doi:10.1007/s002130051034. PMID   10445375. S2CID   20661122.
  3. Pälvimäki EP, Majasuo H, Kuoppamäki M, Männistö PT, Syvälahti E, Hietala J (March 1998). "Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation". Psychopharmacology. 136 (2): 99–104. doi:10.1007/s002130050544. PMID   9551765. S2CID   33983579.
  4. Kovács I, Maksay G, Simonyi M (March 1989). "Inhibition of high-affinity synaptosomal uptake of gamma-aminobutyric acid by a bicyclo-heptane derivative". Arzneimittel-Forschung. 39 (3): 295–7. PMID   2502985.
  5. Celada P, Puig M, Amargós-Bosch M, Adell A, Artigas F (July 2004). "The therapeutic role of 5-HT1A and 5-HT2A receptors in depression". Journal of Psychiatry & Neuroscience. 29 (4): 252–65. PMC   446220 . PMID   15309042.
  6. Laine K, Ahokoski O, Huupponen R, Hänninen J, Palovaara S, Ruuskanen J, et al. (December 2003). "Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone". European Journal of Clinical Pharmacology. 59 (10): 761–6. doi:10.1007/s00228-003-0674-3. PMID   14566442. S2CID   38235268.
  7. Laine K, De Bruyn S, Björklund H, Rouru J, Hänninen J, Scheinin H, Anttila M (February 2004). "Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics". European Journal of Clinical Pharmacology. 59 (12): 893–8. doi:10.1007/s00228-003-0714-z. PMID   14730412. S2CID   21409667.
  8. 1 2 3 4 5 6 7 8 9 10 Huupponen R, Anttila M, Rouru J, Kanerva H, Miettinen T, Scheinin M (August 2004). "Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers". International Journal of Clinical Pharmacology and Therapeutics. 42 (8): 449–55. doi:10.5414/cpp42449. PMID   15366325.
  9. 1 2 3 4 5 6 Monostory K, Kohalmy K, Ludányi K, Czira G, Holly S, Vereczkey L, et al. (November 2005). "Biotransformation of deramciclane in primary hepatocytes of rat, mouse, rabbit, dog, and human". Drug Metabolism and Disposition. 33 (11): 1708–16. doi:10.1124/dmd.105.003764. PMID   16118331. S2CID   6551928.
  10. 1 2 Naukkarinen H, Raassina R, Penttinen J, Ahokas A, Jokinen R, Koponen H, et al. (December 2005). "Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study". European Neuropsychopharmacology. 15 (6): 617–23. doi:10.1016/j.euroneuro.2005.03.002. PMID   15949921. S2CID   8514329.
  11. 1 2 Blow to Orion as deramciclane fails in Phase III anxiety studies, 2003 http://www.thepharmaletter.com/article/blow-to-orion-as-deramciclane-fails-in-phase-iii-anxiety-studies
  12. 1 2 Drabant S, Nemes KB, Horváth V, Tolokán A, Grézal G, Anttila M, et al. (November 2004). "Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers". European Journal of Pharmaceutics and Biopharmaceutics. 58 (3): 689–95. doi:10.1016/j.ejpb.2004.03.036. PMID   15451546.
  13. 1 2 3 4 5 6 Kanerva H, Kilkku O, Heinonen E, Helminen A, Rouru J, Tarpila S, et al. (October 1999). "The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers". Biopharmaceutics & Drug Disposition. 20 (7): 327–34. doi:10.1002/(SICI)1099-081X(199910)20:7<327::AID-BDD192>3.0.CO;2-8. PMID   10760840. S2CID   32845167.
  14. 1 2 3 4 5 6 Kanerva H, Kilkku O, Helminen A, Rouru J, Scheinin M, Huupponen R, et al. (December 1999). "Pharmacokinetics and safety of deramciclane during multiple oral dosing". International Journal of Clinical Pharmacology and Therapeutics. 37 (12): 589–97. PMID   10599951.
  15. Kertész S, Kapus G, Gacsályi I, Lévay G (February 2010). "Deramciclane improves object recognition in rats: potential role of NMDA receptors". Pharmacology, Biochemistry, and Behavior. 94 (4): 570–4. doi:10.1016/j.pbb.2009.11.012. PMID   19963003. S2CID   27014927.
  16. Huupponen R, Paija O, Salonen M, Björklund H, Rouru J, Anttila M (2003). "Pharmacokinetics of deramciclane, a novel anxiolytic agent, after intravenous and oral administration". Drugs in R&D. 4 (6): 339–45. doi:10.2165/00126839-200304060-00002. PMID   14584962. S2CID   25819561.
  17. 1 2 Nemes KB, Abermann M, Bojti E, Grézal G, Al-Behaisi S, Klebovich I (January 2000). "Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat". The Journal of Pharmacy and Pharmacology. 52 (1): 47–51. doi: 10.1211/0022357001773670 . PMID   10716602. S2CID   40494609.
  18. Foley FW, Traugott U, LaRocca NG, Smith CR, Perlman KR, Caruso LS, Scheinberg LC (March 1992). "A prospective study of depression and immune dysregulation in multiple sclerosis". Archives of Neurology. 49 (3): 238–44. doi:10.1001/archneur.1992.00530270052018. PMID   1536625.