Pharmacodynamics<unk>  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).<unk>  also shows significant affinity for the D3 receptor (Ki = 0.494 nM). 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, though it does possess low affinity for the sigma receptor (IC50 = 286 nM).<unk>  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<unk>  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<unk> 's unique eight membered ring results in the (R) stereoisomer of the compound demonstrating increased affinity for the indicated targets. Receptor Ki nM<unk> * Ki nM (N-deethylblonanserin)* D1 1070 1020 D2 0.142 1.38 D3 0.494 0.23 D4 150 - D5 2600 - 5-HT1A 804 - 5-HT2A 0.812 1.28 5-HT2C 26.4 4.50 5-HT6 11.7 5.03 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<unk>  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. Olanzapine does not appear to affect PKA activity. 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.<unk>  Cartoon<unk>  action at dopamine-D3 receptor. Cartoon of<unk> '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). Pharmacokinetics<unk>  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 of<unk>  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.<unk>  is not a charged compound and exhibits very little chemical polarity. The polar surface area of<unk>  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 so<unk>  is expected to be quite permeable as is demonstrated by a high brain/ plasma ratio of 3.88. Due to the good permeability of<unk> , 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.<unk>  does not meet the criteria in Lipinski's rule of five. Effects of food intake Food intake slows the absorption of<unk>  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<unk>  and Cytochrome P450 3A4 in the gut.
Blonanserin
Ketanserin
Adatanserin
Mianserin
Seltorexant
Flibanserin
Nabilone
Pimavanserin