blonanserin

Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.{{cite journal | vauthors = Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU | title = Asenapine, blonanserin, iloperidone, lurasidone, and sertindole: distinctive clinical characteristics of 5 novel atypical antipsychotics | journal = Clinical Neuropharmacology | volume = 36 | issue = 6 | pages = 223–238 | date = 2013 | pmid = 24201235 | doi = 10.1097/wnf.0b013e3182aa38c4 | s2cid = 21426260 }}

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.

Blonanserin acts as a mixed 5-HT_2A (K_i = 0.812 nM) and D₂ receptor (K_i = 0.142 nM) antagonist and also exerts some blockade of α₁-adrenergic receptors (K_i = 26.7 nM).{{cite journal | vauthors = Tenjin T, Miyamoto S, Ninomiya Y, Kitajima R, Ogino S, Miyake N, Yamaguchi N | title = Profile of blonanserin for the treatment of schizophrenia | journal = Neuropsychiatric Disease and Treatment | volume = 9 | pages = 587–594 | year = 2013 | pmid = 23766647 | pmc = 3677929 | doi = 10.2147/NDT.S34433 | doi-access = free }}{{cite journal | vauthors = Oka M, Noda Y, Ochi Y, Furukawa K, Une T, Kurumiya S, Hino K, Karasawa T | display-authors = 6 | title = Pharmacological profile of AD-5423, a novel antipsychotic with both potent dopamine-D2 and serotonin-S2 antagonist properties | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 264 | issue = 1 | pages = 158–165 | date = January 1993 | pmid = 8093723 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8093723 }} Blonanserin also shows significant affinity for the D₃ receptor (K_i = 0.494 nM).{{cite journal | vauthors = Hida H, Mouri A, Mori K, Matsumoto Y, Seki T, Taniguchi M, Yamada K, Iwamoto K, Ozaki N, Nabeshima T, Noda Y | display-authors = 6 | title = Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC | journal = Neuropsychopharmacology | volume = 40 | issue = 3 | pages = 601–613 | date = February 2015 | pmid = 25120077 | pmc = 4289947 | doi = 10.1038/npp.2014.207 }} It lacks significant affinity for numerous other sites including the 5-HT_1A, 5-HT₃, D₁, α₂-adrenergic, β-adrenergic, H₁, and mACh receptors and the monoamine transporters, 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.{{cite journal | vauthors = Suzuki K, Hiyama Y, Une T, Fujiwara I | title = Crystal structure of an antipsychotic agent, 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (blonanserin) | journal = Analytical Sciences | volume = 18 | issue = 11 | pages = 1289–1290 | date = November 2002 | pmid = 12458724 | doi = 10.2116/analsci.18.1289 | doi-access = free }} 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.{{cite journal | vauthors = Ochi T, Sakamoto M, Minamida A, Suzuki K, Ueda T, Une T, Toda H, Matsumoto K, Terauchi Y | display-authors = 6 | title = Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 4 | pages = 1055–1059 | date = February 2005 | pmid = 15686911 | doi = 10.1016/j.bmcl.2004.12.028 }}

* Towards human receptors unless otherwise specified.

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.{{cite journal | vauthors = Yokota K, Tatebayashi H, Matsuo T, Shoge T, Motomura H, Matsuno T, Fukuda A, Tashiro N | display-authors = 6 | title = The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics | journal = British Journal of Pharmacology | volume = 135 | issue = 6 | pages = 1547–1555 | date = March 2002 | pmid = 11906969 | pmc = 1573270 | doi = 10.1038/sj.bjp.0704608 }} Olanzapine does not appear to affect PKA activity.{{cite journal | vauthors = Nagai T, Noda Y, Une T, Furukawa K, Furukawa H, Kan QM, Nabeshima T | title = Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice | journal = NeuroReport | volume = 14 | issue = 2 | pages = 269–272 | date = February 2003 | pmid = 12598744 | doi = 10.1097/00001756-200302100-00023 | s2cid = 41717348 }} Many antipsychotics, such as haloperidol, chlorpromazine, risperidone and olanzapine primarily antagonize serotonin 5-HT2A and dopamine-D₂ receptors and lack known action at dopamine-D_2/3 receptors.

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.{{cite journal | vauthors = Chen X, Wang H, Jiang J, Chen R, Zhou Y, Zhong W, Liu H, Hu P | display-authors = 6 | title = The pharmacokinetic and safety profiles of blonanserin in healthy Chinese volunteers after single fasting doses and single and multiple postprandial doses | journal = Clinical Drug Investigation | volume = 34 | issue = 3 | pages = 213–222 | date = March 2014 | pmid = 24399453 | doi = 10.1007/s40261-013-0167-9 | s2cid = 35831132 }} The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination.{{cite journal | vauthors = Wen YG, Shang DW, Xie HZ, Wang XP, Ni XJ, Zhang M, Lu W, Qiu C, Liu X, Li FF, Li X, Luo FT | display-authors = 6 | title = Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake | journal = Human Psychopharmacology | volume = 28 | issue = 2 | pages = 134–141 | date = March 2013 | pmid = 23417765 | doi = 10.1002/hup.2290 | s2cid = 12623938 }} The half-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of {{nobr|7.7 ± 4.63 h}} and a single dose of 8 mg has a half-life of {{nobr|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. The polar surface area of Blonanserin is 19.7 Å{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/Blonanserin|title=Blonanserin | work = PubMed | publisher = U.S. National Library of Medicine }} 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.{{cite journal | vauthors = Tateno A, Arakawa R, Okumura M, Fukuta H, Honjo K, Ishihara K, Nakamura H, Kumita S, Okubo Y | display-authors = 6 | title = Striatal and extrastriatal dopamine D2 receptor occupancy by a novel antipsychotic, blonanserin: a PET study with [11C]raclopride and [11C]FLB 457 in schizophrenia | journal = Journal of Clinical Psychopharmacology | volume = 33 | issue = 2 | pages = 162–169 | date = April 2013 | pmid = 23422369 | doi = 10.1097/jcp.0b013e3182825bce | s2cid = 33775568 }}

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.

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

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 in the gut.

• Dopamine receptor D₃
• Lipinski's rule of five

{{Reflist|2}}

{{Antipsychotics}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

Category:5-HT2 antagonists

Category:Atypical antipsychotics

Category:D2 antagonists

Category:D3 antagonists

Category:4-Fluorophenyl compounds

Category:Piperazines