Blonanserin
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Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic (approved by PMDA in January 2008)[1] commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia.[2] Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension.[3] 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.[4]
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Medical uses
Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.[5]
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.[4]
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).[6][7] Blonanserin also shows significant affinity for the D3 receptor (Ki = 0.494 nM).[8] 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,[7] though it does possess low affinity for the sigma receptor (IC50 = 286 nM).[7]
Blonanserin has a relatively high affinity towards the 5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia.[6] The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics.[9] 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.[10]
| Receptor | Ki [nM] (Blonanserin)* [6] | Ki [nM] (N-deethylblonanserin)* [2] |
|---|---|---|
| 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.
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.[8][11] Olanzapine does not appear to affect PKA activity.[8][12] 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.[8][9]
| Blonanserin Cartoon |
| 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).[8][11] |
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.[13] The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination.[14] 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.[13] 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.[13]
Blonanserin is not a charged compound and exhibits very little chemical polarity. The polar 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 the blood 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, 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.[14]
Blonanserin does not meet the criteria in Lipinski's rule of five.[15]
Effects of food intake
Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally.[14] 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.[13]
See also
References
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Template:Dopamine receptor modulators Template:Serotonin receptor modulators