| Iupac Name: | 2-(4-ethylpiperazin-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine |
| Width: | 260 |
| Width2: | 260 |
| Tradename: | Lonasen |
| Legal Status: | Rx-only |
| Routes Of Administration: | By mouth |
| Bioavailability: | 55%[1] |
| Metabolism: | CYP3A4 |
| Elimination Half-Life: | 12 h |
| Excretion: | 59% (urine), 30% (faeces) |
| Cas Number: | 132810-10-7 |
| Atc Prefix: | none |
| Pubchem: | 125564 |
| Chembl: | 178803 |
| Chemspiderid: | 111697 |
| Unii: | AQ316B4F8C |
| Kegg: | D01176 |
| C: | 23 |
| H: | 30 |
| F: | 1 |
| N: | 3 |
| Smiles: | 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]
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 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]
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] 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)* | Ki [nM] (N-deethylblonanserin)* | |
|---|---|---|---|
| 1070 | 1020 | ||
| 0.142 | 1.38 | ||
| 0.494 | 0.23 | ||
| 150 | - | ||
| 2600 | - | ||
| 804 | - | ||
| 0.812 | 1.28 | ||
| 26.4 | 4.50 | ||
| 11.7 | 5.03 | ||
| 183 | - | ||
| 26.7 (Rat brain) | 206 (Rat receptor) | ||
| 530 (Rat cloned) | - | ||
| 100 | - | ||
| 765 | - |
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] [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]
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.[15] The half-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of and a single dose of 8 mg has a half-life of .[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 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]
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.[14]