Brexpiprazole

Pharmacodynamics

Brexpiprazole acts as a partial agonist of the serotonin 5-HT_1A receptor and the dopamine D₂ and D₃ receptors.^[26] Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness.^[26] Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D₂ receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist is considered to terminate its motoric side effects due to their agonistic behaviour which gets suppressed earlier with lower dosages when they have less intrinsic value. This is also the reason (nevertheless with the seemingly against-decided competition in the antipsychotic of choice, and this also with the fact, that brexpiprazole fell into the age of development having much more information privileges of considering and adjust of its maximum recommended dose, right under before it went off-label) why through its significant lower value than all other neuroleptics from the 3rd generation (e.g. cariprazine(D3,70% for example), it could be considered as working with some similar efficacy than a full antagonist (like perphenazine) at the D2 receptor, so a receptor occupation of only 68+% at the maximum recommended dose is seen enough (compared with the necessary occupation of 90% at the D2 receptor when administered aripiprazole or cariprazine). What is being surprisingly is to did the effort of evaluating this molecules all nanoMolar affinitys in with at development, because yet, (like transporteraffinity, one can also see in ziprasidone for example) some antipsychotics are capable of blocking transporters. But it turned out that (also together with ziprasidones also weak nanoMolar ability of 112) brexpiprazole has just the weak DAT-transporter nanoMolar affinity of the multiple of 0.8 compared with its affinity at dopamin D2 receptors (meaning that there has to be the 8-fold of the maximum recommended dose to be as sufficient as at this transporters then brexpiprazole does on postsynaptic D2-dopaminreceptors).^{[29][30][31][32][33][34][35][36][37][38]} Brexpiprazole has a high affinity for the 5-HT_1A receptor, acting as a potent antagonist at 5-HT_2A receptors, and a potent partial agonist at dopamine D₂ receptors with lower intrinsic activity compared to aripiprazole.^[39] In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the 5-HT_1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT_1A receptor agonism. It is also an antagonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT₇ receptors, which may contribute to antidepressant effect. It also binds to and blocks the α_1A-, α_1B-, α_1D-, and α_2C-adrenergic receptors.^[26] The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects.^[26] Although brexpiprazole has less affinity for H₁ compared to aripiprazole, weight gain can occur.^[40]

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder,^[41] schizophrenia,^[42] and agitation associated with dementia due to Alzheimer's disease.^[13]

Legal status

In January 2018, it was approved for the treatment of schizophrenia in Japan.^[52]

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.^[53]

Patents

• U.S. patent 8,071,600
• WIPO PCT/JP2006/317704
• Canadian patent: 2620688^[54]