Blonanserin, sold under the brand name Lonasen, is a relatively new

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...

(approved by PMDA in January 2008) commercialized by

Dainippon Sumitomo Pharma is a pharmaceutical company based in Japan. Its headquarters are in Chuo-ku, Osaka. The original Dainippon Pharmaceuticals (Dainippon Seiyaku) was established in 1885 by Nagayo Sensai, a graduate of Tekijuku – the first private medical scho ...

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the n ...

and

Korea Korea ( ko, 한국, or , ) is a peninsular region in East Asia. Since 1945, it has been divided at or near the 38th parallel, with North Korea (Democratic People's Republic of Korea) comprising its northern half and South Korea (Republic ...

for the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s such as extrapyramidal symptoms, excessive

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

, or

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

. 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.

Medical uses

Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.

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 A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...

levels,

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

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.

Pharmacology

Pharmacodynamics

Blonanserin acts as a mixed 5-HT_2A (K_i = 0.812 nM) and D₂ receptor (K_i = 0.142 nM)

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

and also exerts some blockade of α₁-adrenergic receptors (K_i = 26.7 nM). Blonanserin also shows significant affinity for the D₃ receptor (K_i = 0.494 nM). It lacks significant affinity for numerous other sites including the 5-HT_1A, 5-HT₃, D₁, α₂-adrenergic,

β-adrenergic The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

, H₁, and mACh receptors and the

monoamine transporter Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible fo ...

s, 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. * Towards human receptors unless otherwise specified.

Action at the Dopamine-D₃ receptor

Blonanserin has antagonistic action at dopamine-D₃ receptors that potentiates

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

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 Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is t ...

does not appear to affect PKA activity. Many antipsychotics, such as haloperidol, chlorpromazine,

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...

and olanzapine primarily antagonize serotonin 5-HT2A and dopamine-D₂ receptors and lack known action at dopamine-D_2/3 receptors.

Pharmacokinetics

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 Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

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 In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end. Polar molecules must contain one or more polar ...

. 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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ...

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 pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

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. Blonanserin does not meet the criteria in Lipinski's rule of five.

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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

in the gut.

References

{{Serotonin receptor modulators 5-HT2 antagonists Atypical antipsychotics D2 antagonists D3 antagonists Fluoroarenes Piperazines