Blonanserin

Last updated
Blonanserin
Blonanserin.svg
Blonanserin-xtal-2012-ball-and-stick.png
Clinical data
Trade names Lonasen
Routes of
administration 		By mouth
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55% [1]
Metabolism CYP3A4 [1]
Elimination half-life 12 h [1]
Excretion 59% (urine), 30% (faeces) [1]
Identifiers
  • 2-(4-ethylpiperazin-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.211.656 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H30FN3
Molar mass 367.512 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)c2cc(nc3c2CCCCCC3)N4CCN(CC)CC4

Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic (approved by PMDA in January 2008) [2] commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. [3] Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. [4] As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol. [5]

Contents

Medical uses

Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US. [6]

Adverse effects

As with many of the atypical antipsychotics, blonanserin can elicit cardio metabolic risks. While the side effects of blonanserin – such as weight gain, cholesterol and triglyceride levels, glucose levels and other blood lipid levels – do not differ greatly from other atypical antipsychotics, the specificity of blonanserin appears to elicit milder side effects, with less weight gain in particular. [5]

Pharmacology

Pharmacodynamics

Blonanserin acts as a mixed 5-HT2A (Ki = 0.812 nM) and D2 receptor (Ki = 0.142 nM) antagonist and also exerts some blockade of α1-adrenergic receptors (Ki = 26.7 nM). [7] [8] Blonanserin also shows significant affinity for the D3 receptor (Ki = 0.494 nM). [9] It lacks significant affinity for numerous other sites including the 5-HT1A, 5-HT3, D1, α2-adrenergic, β-adrenergic, H1, and mACh receptors and the monoamine transporters, [8] though it does possess low affinity for the sigma receptor (IC50 = 286 nM). [8]

Blonanserin has a relatively high affinity towards the 5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia. [7] [10] The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics. [11] Specifically, the addition of hydroxyl groups to blonanserin's unique eight membered ring results in the (R) stereoisomer of the compound demonstrating increased affinity for the indicated targets. [12]

ReceptorKi [nM] (Blonanserin)* [7] Ki [nM] (N-deethylblonanserin)* [3]
D1 10701020
D2 0.1421.38
D3 0.4940.23
D4 150-
D5 2600-
5-HT1A 804-
5-HT2A 0.8121.28
5-HT2C 26.44.50
5-HT6 11.75.03
5-HT7 183-
α1 26.7 (Rat brain)206 (Rat receptor)
α2 530 (Rat cloned)-
M1 100-
H1 765-

* Towards human receptors unless otherwise specified.

Action at the Dopamine-D3 receptor

Blonanserin has antagonistic action at dopamine-D3 receptors that potentiates phosphorylation levels of Protein kinase A (PKA) and counteracts decreased activity at the dopamine-D1 and/or NMDA receptors, thus potentiating GABA induced Cl- currents. [9] [13] Olanzapine does not appear to affect PKA activity. [9] [14] Many antipsychotics, such as haloperidol, chlorpromazine, risperidone and olanzapine primarily antagonize serotonin 5-HT2A and dopamine-D2 receptors and lack known action at dopamine-D2/3 receptors. [9] [11]

Blonanserin Cartoon.jpg
Blonanserin action at dopamine-D3 receptor. Cartoon of blonanserin's antagonistic impact at the dopamine-D3 receptor, reversing inhibition of PKA activity (also regulated by dopamine-D1 and NMDA activity) thus potentiating GABA induced Cl- current. Inset illustrates uninterrupted dopamine (DA) activity at the dopamine-D3 receptor. Inspired by Hida et al. (2014) and Yokota et al. (2002). [9] [13]

Pharmacokinetics

Blonanserin is administered 4 mg orally twice a day or 8 mg once a day, for an adult male with a body mass index between 19–24 kg/m2 and a body weight equal to or greater than 50 kg. [15] The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination. [1] The half-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of 7.7 ± 4.63 h and a single dose of 8 mg has a half-life of 11.9 ± 4.3 h. [15] The increase of half-life with dose is possibly attributed to there being more individual concentration per time points below the lower limit necessary for quantification in the lower single dose. [15]

Blonanserin is not a charged compound and exhibits very little chemical polarity. The polar surface area of Blonanserin is 19.7 Å [16] It is commonly accepted that a compound needs to have polar surface area less than 90 Å to cross the blood brain barrier so blonanserin is expected to be quite permeable as is demonstrated by a high brain/ plasma ratio of 3.88. [17]

Due to the good permeability of blonanserin, the volume of distribution in the central nervous system is greater than that in the periphery (Vd central = 9500 L, Vd periphery = 8650 L) although it is slower to absorb into the central compartment. [1]

Blonanserin does not meet the criteria in Lipinski's rule of five. [16]

Effects of food intake

Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally. [1] Single fasting doses are safe and the effects of feeding intake are possibly explained by an interaction between blonanserin and Cytochrome P450 3A4 in the gut. [15]

See also

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References

  1. 1 2 3 4 5 6 7 Wen YG, Shang DW, Xie HZ, Wang XP, Ni XJ, Zhang M, et al. (March 2013). "Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake". Human Psychopharmacology. 28 (2): 134–141. doi:10.1002/hup.2290. PMID   23417765. S2CID   12623938.
  2. ↑ "FY2007 List of Approved Products: New Drugs" (PDF). Tokyo, Japan: Pharmaceuticals and Medical Devices Agency. Archived from the original (PDF) on 2013-01-19. Retrieved 2013-08-16.
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  4. ↑ Heading CE (November 1998). "AD-5423 Dainippon Pharmaceutical Co Ltd". IDrugs. 1 (7): 813–817. PMID   18465651.
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  6. ↑ Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU (2013). "Asenapine, blonanserin, iloperidone, lurasidone, and sertindole: distinctive clinical characteristics of 5 novel atypical antipsychotics". Clinical Neuropharmacology. 36 (6): 223–238. doi:10.1097/wnf.0b013e3182aa38c4. PMID   24201235. S2CID   21426260.
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  9. 1 2 3 4 5 Hida H, Mouri A, Mori K, Matsumoto Y, Seki T, Taniguchi M, et al. (February 2015). "Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC". Neuropsychopharmacology. 40 (3): 601–613. doi:10.1038/npp.2014.207. PMC   4289947 . PMID   25120077.
  10. ↑ Tenjin T, Miyamoto S, Miyake N, Ogino S, Kitajima R, Ojima K, et al. (January 2012). "Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia". Human Psychopharmacology. 27 (1): 90–100. doi:10.1002/hup.1276. PMID   22278973. S2CID   205925034.
  11. 1 2 Suzuki K, Hiyama Y, Une T, Fujiwara I (November 2002). "Crystal structure of an antipsychotic agent, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (blonanserin)". Analytical Sciences. 18 (11): 1289–1290. doi: 10.2116/analsci.18.1289 . PMID   12458724.
  12. ↑ Ochi T, Sakamoto M, Minamida A, Suzuki K, Ueda T, Une T, et al. (February 2005). "Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent". Bioorganic & Medicinal Chemistry Letters. 15 (4): 1055–1059. doi:10.1016/j.bmcl.2004.12.028. PMID   15686911.
  13. 1 2 Yokota K, Tatebayashi H, Matsuo T, Shoge T, Motomura H, Matsuno T, et al. (March 2002). "The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics". British Journal of Pharmacology. 135 (6): 1547–1555. doi:10.1038/sj.bjp.0704608. PMC   1573270 . PMID   11906969.
  14. ↑ Nagai T, Noda Y, Une T, Furukawa K, Furukawa H, Kan QM, Nabeshima T (February 2003). "Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice". NeuroReport. 14 (2): 269–272. doi:10.1097/00001756-200302100-00023. PMID   12598744. S2CID   41717348.
  15. 1 2 3 4 Chen X, Wang H, Jiang J, Chen R, Zhou Y, Zhong W, et al. (March 2014). "The pharmacokinetic and safety profiles of blonanserin in healthy Chinese volunteers after single fasting doses and single and multiple postprandial doses". Clinical Drug Investigation. 34 (3): 213–222. doi:10.1007/s40261-013-0167-9. PMID   24399453. S2CID   35831132.
  16. 1 2 "Blonanserin". PubMed. U.S. National Library of Medicine.
  17. ↑ Tateno A, Arakawa R, Okumura M, Fukuta H, Honjo K, Ishihara K, et al. (April 2013). "Striatal and extrastriatal dopamine D2 receptor occupancy by a novel antipsychotic, blonanserin: a PET study with [11C]raclopride and [11C]FLB 457 in schizophrenia". Journal of Clinical Psychopharmacology. 33 (2): 162–169. doi:10.1097/jcp.0b013e3182825bce. PMID   23422369. S2CID   33775568.
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