Blonanserin

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).[7][8] Blonanserin also shows significant affinity for the D₃ receptor (K_i = 0.494 nM).[9] 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,[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]

* 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.[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-D_2/3 receptors.[9][11]

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]

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.[15] The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination.[16] 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[17] 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.[18]

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.[16]

Blonanserin does not meet the criteria in Lipinski's rule of five.[17]

Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally.[16] 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]