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 tranquilizers and neurol ...

(approved by PMDA in January 2008) commercialized by

Dainippon Sumitomo Pharma is a Japanese multinational pharmaceutical company. The company is focused on oncology, psychiatry, neurology, women's health issues, urological diseases among other areas. Its headquarters are located in Chuo-ku, Osaka. History The original ...

Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

and

Korea Korea is a peninsular region in East Asia consisting of the Korean Peninsula, Jeju Island, and smaller islands. Since the end of World War II in 1945, it has been politically Division of Korea, divided at or near the 38th parallel north, 3 ...

for the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. Relative to many other antipsychotics, blonanserin has an improved

tolerability In pharmacology, tolerability refers to the degree to which overt adverse effects of a drug can be tolerated by a patient. Tolerability of a particular drug can be discussed in a general sense, or it can be a quantifiable measurement as part of a ...

profile, lacking

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s such as

extrapyramidal symptom Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...

s, 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, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the

negative symptoms Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

of schizophrenia compared to first-generation (typical) antipsychotics such as

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

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

levels,

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

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 main enemy or rival of the protagonist and is often depicted as a villain.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 Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

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 proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s, though it does possess low affinity for the

sigma receptor Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 rec ...

(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 biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

levels of

Protein kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

(PKA) and counteracts decreased activity at the dopamine-D₁ and/or

NMDA ''N''-methyl--aspartic acid, or ''N''-methyl--aspartate (NMDA), is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unl ...

receptors, thus potentiating

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

induced Cl- currents.

Olanzapine Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomitin ...

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

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

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 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. The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination. The

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''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 . 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 The polar surface area (PSA) or topological polar surface area (TPSA) of a molecule is defined as the surface sum over all polar atoms or molecules, primarily oxygen and nitrogen, also including their attached hydrogen atoms. PSA is a commonly us ...

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 is compo ...

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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

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, which in humans is encoded by ''CYP3A4'' gene. It oxidizes small foreign organic molecules (xenobiotics), such as t ...

in the gut.

References

{{Serotonin receptor modulators 5-HT2 antagonists Atypical antipsychotics D2 antagonists D3 antagonists 4-Fluorophenyl compounds Piperazines