Asenapine

Asenapine

Systematic (IUPAC) name
(3aS,12bS)-rel-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 Y
UNII	JKZ19V908O Y
ChEMBL	CHEMBL1201756 N
Chemical data
Formula	C17H16ClNO
Mol. mass	285.77 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m0/s1 Y Key:VSWBSWWIRNCQIJ-GJZGRUSLSA-N Y
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. 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.

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)

Pharmacology

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT_1A (8.6), 5-HT_1B (8.4), 5-HT_2A (10.2), 5-HT_2B (9.8), 5-HT_2C (10.5), 5-HT_5A (8.8), 5-HT₆ (9.5), and 5-HT₇ (9.9) receptors, the adrenergic α₁ (8.9), α_2A (8.9), α_2B (9.5), and α_2C (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. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as an a partial agonist at the 5-HT_1A and D₁ receptors. At all other targets Asenapine is an antagonist. As of November 2010 Asenapine is also in clinical trials at UC Irvine to treat stuttering.

Receptor	Affinity (pKi)	Affinity (Ki (nM))
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

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.

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.

Synthesis

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

Reduction step is sodium in liquid ammonia.

External links

• Saphris website
• Organon website
• Organon Continues With The Development Of Asenapine For Schizophrenia And Acute Mania Associated With Bipolar I Disorder