Dopamine antagonist

D1-like receptors – D₁ and D₅ are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.

• D₁ receptors are found mainly on neurons in the nucleus accumbens[3] as well as substantia nigra,[2] striatum,[2] amygdala,[2] frontal cortex[2] and olfactory bulb and retina[2]
• Also found (in lower levels) in the hypothalamus, thalamus, cerebellum and hippocampus[2]
• Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation.[4] In addition, D₁ receptors have been found in the kidney[4]

• Low levels of D₅ receptors have been found in the hypothalamus, prefrontal cortex and cingulate cortex; as well as memory areas such as hippocampus, dentate gyrus and entorhinal cortex.[2]
• In addition, D₅ receptors have been found in the kidney[4]

D₂-like receptors unlike the D₁-like class, these receptors are found pre and post-synaptically. The genes that code these receptors have introns, leading to many alternately spliced variants.

• D₂ receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tubercle.[2]
• These receptors have also been found in the retina and pituitary gland.[2]
• Peripherally, these receptors have been found in the renal, mesenteric, and splenic arteries as well as on the adrenal cortex and medulla and within the kidney.[4]

• D₃ receptors are highly expressed on neurons in islands of Calleja and nucleus accumbens shell and lowly expressed in areas such as the substantia nigra pars compacta, hippocampus, septal area, and ventral tegmental area.[2][3]
• Additional studies have found these receptors peripherally in the kidney[4]

• D₄ receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney[2][4]

First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects.[19] They inhibit dopaminergic neurotransmission in the brain by blocking about 72% of the D2 dopamine receptors.[20] They can also block noradrenergic, cholinergic, and histaminergic activity.[20]

• Benperidol[19] binds D₂ and some serotonin receptors.[21] It is absorbed very easily and has a high first pass effect.[21]
• Chlorpromazine binds D₃ with the highest affinity, but also binds D₁, D₂, D₄ and D₅[22][23]

Chemical Structure of typical antipsychotic chlorpromazine

• Clopenthixol[19]
• Droperidol is used as an antipsychotic and antiemetic.[19]
• Haloperidol binds D₂, D₃ and D₄ with the highest affinity, but also binds D₁ and D_5.[19][22][23] Haloperidol also has a risk for QTc prolongation. [24]
• Fluphenazine binds D₂ and D₃ with the highest affinity but D₁ and D₅ as well[19][22]
• Flupentixol binds D₁, D₂, D₃, and D₅[22] and is also used as an antidepressant.[19]
• Fluspirilene[19]
• Penfluridol[19]
• Perazine[19]

• Perphenazine[19]
• Pimozide binds D₂ and D₃ with high affinity, also binds D₄ receptors[19][22]

• Spiperone binds D₂, D₃ and D₄ with high affinity; can also bind D₁[19][22]

• Sulpiride binds D₂ and D₃[19][22] and is also used as an antidepressant.[19]
• Thioridazine binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅ at higher concentrations[22] Thioridazine has the highest associated risk of QTc prolongation among neuroleptics.[24]

These drugs are not only dopamine antagonists at the receptor specified, but also act on serotonin receptor 5HT_2A.[20][25] (Citation inappropriate) These drugs have less extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics.[26]

• Amisulpride binds D₂ and D₃[27] and is used as an antipsychotic, antidepressant and also treats bipolar disorder.[25] It treats both the positive and negative symptoms of schizophrenia.[28]
• Asenapine binds D₂, D₃ and D₄[29] and is used to treat bipolar disorder and schizophrenia.[30] Its side effects include weight gain but there is lower risk for orthostatic hypotension and hyperprolactinemia.
• Aripiprazole binds D₂ as a partial agonist but antagonizes D_3.[31] In addition, aripiprazole treats schizophrenia, bipolar disorder (mania),[32] depression,[25] and tic disorders[31]

Clozapine

• Clozapine binds D₁ and D₄ with the highest affinity but still binds D₂ and D₃.[33] Clozapine is unique because it is only prescribed when treatment with at least two other antipsychotics has failed due to its very harsh side effects.[34] It also requires weekly white blood cell counts to monitor potential neutropenia.[34]

• Loxapine binds D₂, D₃ and D₄ with high affinity; can also bind D_1.[35] Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia.[36]
• Nemonapride binds D₃, D₄ and D_5.[37]
• Olanzapine binds all receptors[38] and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression.[39] It has been associated with significant weight gain.[40]

• Quetiapine binds D₁, D₂ and D₃ and can bind D₄ at high concentrations.[38] It is used to treat the positive symptoms of schizophrenia,[40] bipolar disorder and depression.[39] Of the second generation antipsychotics, quetiapine may produce fewer parkinsonian side effects.[41]
• Paliperidone binds D₂, D₃ and D₄ with high affinity; can also bind D₁ and D₅.[42]

• Remoxipride binds D₂ receptors with relatively low affinity.[38][43][39]
• Risperidone binds D₂, D₃ and D₄ receptors.[39][38][42] Risperidone not only treats the positive and negative symptoms of schizophrenia[40] but also treats bipolar disorder.[39]

• Tiapride blocks D₂ and D₃ and is used as an antipsychotic.[39] It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.[44]
• Ziprasidone blocks the D₂ receptor[45] and is used to treat schizophrenia, depression and bipolar disorder.[39] There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects.[40] Ziprasidone can also cause QTc prolongation.[24]

• Domperidone is a peripherally selective dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent and galactagogue.
• Bromopride binds enteric D₂ receptors[46] and also treats gastroparesis.[47]
• Metoclopramide also treats gastroparesis[47]

• Eticlopride binds D₂ and D₃ with high affinity but also binds D4[48][49][50]
• Nafadotride binds D₂ and D₃[47][48][49]
• Raclopride binds D₂ and D₃[47][48] and can be radiolabeled and used in PET imaging to identify disease progression in Huntington's Disease[51]