|Elimination half-life||12 h|
|Excretion||59% (urine), 30% (faeces)|
|Chemical and physical data|
|Molar mass||367.50 g/mol g·mol−1|
|3D model (JSmol)|
Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic (approved by PMDA in January 2008) commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. 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.
Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.
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.
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). Blonanserin also shows significant affinity for the D3 receptor (Ki = 0.494 nM). 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, though it does possess low affinity for the sigma receptor (IC50 = 286 nM).
Blonanserin has a relatively high affinity towards the 5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia. The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics. 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.
|Receptor||Ki [nM] (Blonanserin)* ||Ki [nM] (N-deethylblonanserin)* |
|α1||26.7 (Rat brain)||206 (Rat receptor)|
|α2||530 (Rat cloned)||-|
* 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. Olanzapine does not appear to affect PKA activity. 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.
|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).|
Blonanserin is administered 4 mg orally 2 times 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. The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination. 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. 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.
Blonanserin is not a charged compound and exhibits very little chemical polarity. The polar surface area of Blonanserin is 19.7 Å 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.
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.
Effects of food intake
Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally. 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.
- Wen, YG; Shang, DW; Xie, HZ; Wang, XP; Ni, XJ; Zhang, M; Lu, W; Qiu, C; Liu, X; Li, FF; Li, X; Luo, FT (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.
- "Archived copy" (PDF). Archived from the original (PDF) on 2013-01-19. Retrieved 2013-08-16.CS1 maint: Archived copy as title (link)
- Deeks, ED; Keating, GM (January 2010). "Blonanserin A Review of its Use in the Management of Schizophrenia". CNS Drugs. 24 (1): 65–84. doi:10.2165/11202620-000000000-00000. PMID 20030420.
- Heading CE (November 1998). "AD-5423 (Dainippon Pharmaceutical Co Ltd)". IDrugs : The Investigational Drugs Journal. 1 (7): 813–7. PMID 18465651.
- Kishi, T; Matsuda, Y; Nakamura, H; Iwata, N (Feb 2013). "Blonanserin for schizophrenia: Systematic review and meta-analysis of double-blind, randomized, controlled trials". Journal of Psychiatric Research. 47 (2): 149–54. doi:10.1016/j.jpsychires.2012.10.011. PMID 23131856.
- 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): 223–38. doi:10.1097/wnf.0b013e3182aa38c4. PMID 24201235.
- Tenjin, T; Miyamoto, S; Ninomiya, Y; Kitajima, R; Ogino, S; Miyake, N; Yamaguchi, N (2013). "Profile of blonanserin for the treatment of schizophrenia". Neuropsychiatric Disease and Treatment. 9: 587–594. doi:10.2147/NDT.S34433. PMC 3677929. PMID 23766647.
- Oka M, Noda Y, Ochi Y, et al. (January 1993). "Pharmacological profile of AD-5423, a novel antipsychotic with both potent dopamine-D2 and serotonin-S2 antagonist properties". The Journal of Pharmacology and Experimental Therapeutics. 264 (1): 158–65. PMID 8093723.
- Hida, H; Mouri, A; Mori, K; Matsumoto, Y; Seki, T; Taniguchi, M; Yamada, K; Iwamoto, K; Ozaki, N; Nabeshima, T; Noda, Y (14 August 2014). "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): 601–13. doi:10.1038/npp.2014.207. PMC 4289947. PMID 25120077.
- Tenjin, T; Miyamoto, S; Miyake, N; Ogino, S; Kitajima, R; Ojima, K; Arai, J; Teramoto, H; Tsukahara, S; Ito, Y; Tadokoro, M; Anai, K; Funamoto, Y; Kaneda, Y; Sumiyoshi, T; Yamaguchi, N (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.
- 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): 1289–90. doi:10.2116/analsci.18.1289. PMID 12458724.
- Ochi, T; Sakamoto, M; Minamida, A; Suzuki, K; Ueda, T; Une, T; Toda, H; Matsumoto, K; Terauchi, Y (15 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): 1055–9. doi:10.1016/j.bmcl.2004.12.028. PMID 15686911.
- Yokota, K; Tatebayashi, H; Matsuo, T; Shoge, T; Motomura, H; Matsuno, T; Fukuda, A; Tashiro, N (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): 1547–55. doi:10.1038/sj.bjp.0704608. PMC 1573270. PMID 11906969.
- Nagai, T; Noda, Y; Une, T; Furukawa, K; Furukawa, H; Kan, QM; Nabeshima, T (10 February 2003). "Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice". NeuroReport. 14 (2): 269–72. doi:10.1097/00001756-200302100-00023. PMID 12598744.
- Chen, X; Wang, H; Jiang, J; Chen, R; Zhou, Y; Zhong, W; Liu, H; Hu, P (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): 213–22. doi:10.1007/s40261-013-0167-9. PMID 24399453.
- Wen, YG; Shang, DW; Xie, HZ; Wang, XP; Ni, XJ; Zhang, M; Lu, W; Qiu, C; Liu, X; Li, FF; Li, X; Luo, FT (March 2013). "Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake". Human Psychopharmacology. 28 (2): 134–41. doi:10.1002/hup.2290. PMID 23417765.
- "Properties Viewer"..
- Tateno, A; Arakawa, R; Okumura, M; Fukuta, H; Honjo, K; Ishihara, K; Nakamura, H; Kumita, S; Okubo, Y (Apr 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): 162–9. doi:10.1097/jcp.0b013e3182825bce. PMID 23422369.