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| Clinical data | |
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| Trade names | Lonasen |
| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 55%[1] |
| Metabolism | CYP3A4[1] |
| Eliminationhalf-life | 12 h[1] |
| Excretion | 59% (urine), 30% (faeces)[1] |
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| ECHA InfoCard | 100.211.656 |
| Chemical and physical data | |
| Formula | C23H30FN3 |
| Molar mass | 367.512 g·mol−1 |
| 3D model (JSmol) | |
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Blonanserin, sold under the brand nameLonasen, is a relatively newatypical antipsychotic (approved byPMDA in January 2008)[2] commercialized byDainippon Sumitomo Pharma inJapan andKorea for the treatment ofschizophrenia.[3] Relative to many other antipsychotics, blonanserin has an improvedtolerability profile, lackingside effects such asextrapyramidal symptoms, excessivesedation, orhypotension.[4] As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of thenegative symptoms of schizophrenia compared to first-generation(typical) antipsychotics such ashaloperidol.[5]
Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.[6]
As with many of the atypical antipsychotics, blonanserin can elicit cardio metabolic risks. While the side effects of blonanserin – such as weight gain, cholesterol andtriglyceride 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]
Blonanserin acts as a mixed5-HT2A (Ki = 0.812 nM) andD2 receptor (Ki = 0.142 nM)antagonist and also exerts some blockade ofα1-adrenergic receptors (Ki = 26.7 nM).[7][8] Blonanserin also shows significant affinity for theD3 receptor (Ki = 0.494 nM).[9] It lacks significantaffinity for numerous other sites including the5-HT1A,5-HT3,D1,α2-adrenergic,β-adrenergic,H1, andmACh receptors and themonoamine transporters,[8] though it does possess low affinity for thesigma receptor (IC50 = 286 nM).[8]
Blonanserin has a relatively high affinity towards the5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia.[7] The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics.[10] 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.[11]
| Receptor | Ki [nM] (Blonanserin)*[7] | Ki [nM] (N-deethylblonanserin)*[3] |
|---|---|---|
| D1 | 1070 | 1020 |
| D2 | 0.142 | 1.38 |
| D3 | 0.494 | 0.23 |
| D4 | 150 | - |
| D5 | 2600 | - |
| 5-HT1A | 804 | - |
| 5-HT2A | 0.812 | 1.28 |
| 5-HT2C | 26.4 | 4.50 |
| 5-HT6 | 11.7 | 5.03 |
| 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.
Blonanserin has antagonistic action at dopamine-D3 receptors that potentiatesphosphorylation levels ofProtein kinase A (PKA) and counteracts decreased activity at the dopamine-D1 and/orNMDA receptors, thus potentiatingGABA induced Cl- currents.[9][12]Olanzapine does not appear to affect PKA activity.[9][13] 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][10]
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| 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 uninterrupteddopamine (DA) activity at the dopamine-D3 receptor. Inspired by Hida et al. (2014) and Yokota et al. (2002).[9][12] |
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.[14] The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination.[1] Thehalf-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of7.7 ± 4.63 h and a single dose of 8 mg has a half-life of11.9 ± 4.3 h.[14] 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.[14]
Blonanserin is not a charged compound and exhibits very littlechemical polarity. Thepolar surface area of Blonanserin is 19.7 Å[15] It is commonly accepted that a compound needs to have polar surface area less than 90 Å to cross theblood brain barrier so blonanserin is expected to be quite permeable as is demonstrated by a high brain/ plasma ratio of 3.88.[16]
Due to the good permeability of blonanserin, thevolume of distribution in thecentral 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 inLipinski's rule of five.[15]
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 andcytochrome P450 3A4 in the gut.[14]