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Asenapine

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Asenapine
Systematic (IUPAC) name
(3aS,12bS)-5-Chloro-2,3,3a,12b-tetrahydro-
2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a610015
Pregnancy cat. C(US)
Legal status Rx only
Routes sublingual
Pharmacokinetic data
Bioavailability 35% sublingual
Protein binding 95%
Metabolism hepatic
Half-life 24 hours
Excretion 50% in urine, 40% in feces
Identifiers
CAS number 65576-45-6 N
ATC code N05AH05
PubChem CID 3036780
IUPHAR ligand 22
ChemSpider 2300725 YesY
UNII JKZ19V908O YesY
ChEMBL CHEMBL1201756 N
Chemical data
Formula C17H16ClNO 
Mol. mass 285.77 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Asenapine (INN, trade names Saphris, Sycrest) is a new atypical antipsychotic developed for the treatment of schizophrenia and acute mania associated with bipolar disorder by Schering-Plough after its November 19, 2007 merger with Organon International. Development of the drug, through Phase III trials, began while Organon was still a part of Akzo Nobel.[1] Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, as well as minimal weight gain. Over 3000 patients have participated in clinical trials of asenapine, and the FDA accepted the manufacturer's NDA on November 26, 2007 for standard review.[2]

Some American psychiatrists have begun to prescribe the drug to combat veterans with severe PTSD nightmares as an "off-label" use, although this use is not yet allowed by the United States Department of Veterans Administration. (Search "Formulary" at www.va.gov)

Contents

[edit] Pharmacology

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors.[3] It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as an a partial agonist at the 5-HT1A and D1 receptors. At all other targets Asenapine is an antagonist.[3] As of November 2010 Asenapine is also in clinical trials at UC Irvine to treat stuttering.

Receptor Affinity (pKi)[3] Affinity (Ki (nM))[4]
5-HT1A 8.6 2.5
5-HT1B 8.4 4.0
5-HT2A 10.2 0.06
5-HT2B 9.8 0.16
5-HT2C 10.5 0.03
5-HT5A 8.8 1.6
5-HT6 9.5 0.25
5-HT7 9.9 0.13
α1-Adrenergic 8.9 1.2
α2A-Adrenergic 8.9 1.2
α2B-Adrenergic 9.5  ? (~0.25)
α2C-Adrenergic 8.9 1.2
D1 8.9 1.4
D2 8.9 1.3
D3 9.4 0.42
D4 9.0 1.1
H1 9.0 1.0
H2 8.2 6.2
mACh < 5 8,128

[edit] Indications and usage

Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.[4]

[edit] Side effects

Common side effects: (incidence at least 5% or greater and at least twice that for placebo or greater than 10% regardless of placebo rate) Severe akathisia, oral hypoesthesia, somnolence, dizziness, extrapyramidal symptoms other than akathisia, weight gain, insomnia, extreme sedation, headache.

Rare side effects: Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate.), tardive dyskinesia.

The FDA has warned healthcare professionals and patients that serious allergic reactions have been reported with the use of Saphris.Healthcare professionals and patients are encouraged to report adverse events or side effects to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.[5]

[edit] Synthesis

Asenapine scheme.png

J. van der Burg, U.S. Patent 4,145,434.

Reduction step is sodium in liquid ammonia.

[edit] References

  1. ^ "Bipolar Disorder". Clinical Trials Update (Genetic Engineering & Biotechnology News): pp. 52,55. 2007-06-15. 
  2. ^ "Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA" (Press release). Schering-Plough. 2007-11-26. http://www.schering-plough.com/news/news_article.aspx?reqid=1080771. Retrieved 2008-12-29. 
  3. ^ a b c Shahid M, Walker GB, Zorn SH, Wong EH. (2009). "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.". J Psychopharmacol. 23 (1): 65–73. doi:10.1177/0269881107082944. PMID 18308814. 
  4. ^ a b "Saphris (asenapine) prescribing information" (PDF). Schering Corporation. 2009-08-01. http://www.spfiles.com/pisaphrisv1.pdf. Retrieved 2009-09-05. 
  5. ^ http://www.drugs.com/fda/saphris-asenapine-maleate-safety-communication-serious-allergic-reactions-13022.html

[edit] External links

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