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

Related Research Articles

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References

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