Dopamine receptor D2, also known asD2R, is aprotein that, in humans, is encoded by theDRD2gene. After work fromPaul Greengard's lab had suggested thatdopamine receptors were the site of action of antipsychotic drugs, several groups, including those ofSolomon H. Snyder andPhilip Seeman used a radiolabeled antipsychotic drug to identify what is now known as thedopamine D2 receptor.[5] The dopamine D2 receptor is the mainreceptor for mostantipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychoticrisperidone has been determined.[6][7]
The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[17] The short form (D2Sh) is pre-synaptic and functions as anautoreceptor that regulates the levels of dopamine in the synaptic cleft.[17]Agonism of D2sh receptors inhibits dopamine release; antagonism increasesdopaminergic release.[17] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[18]
D2R conformers are equilibrated between two full active (D2HighR) and inactive (D2LowR) states, while in complex with anagonist andantagonist ligand, respectively.
The monomeric inactive conformer of D2R in binding withrisperidone was reported in 2018 (PDB ID: 6CM4). However, the active form which is generally bound to an agonist, is not available yet and in most of the studies thehomology modeling of the structure is implemented. The difference between the active and inactive ofG protein-coupled receptor is mainly observed as conformational changes at the cytoplasmic half of the structure, particularly at thetransmembrane domains (TM) 5 and 6. The conformational transitions occurred at the cytoplasmic ends are due to the coupling ofG protein to the cytoplasmic loop between the TM 5 and 6.[19]
It was observed that either D2R agonist or antagonist ligands revealed betterbinding affinities inside the ligand-binding domain of the active D2R in comparison with the inactive state. It demonstrated that ligand-binding domain of D2R is affected by the conformational changes occurring at the cytoplasmic domains of the TM 5 and 6. In consequence, the D2R activation reflects a positive cooperation on the ligand-binding domain.
In drug discovery studies in order to calculate the binding affinities of the D2R ligands inside the binding domain, it's important to work on which form of D2R. It's known that the full active and inactive states are recommended to be used for the agonist and antagonist studies, respectively.
Any disordering in equilibration of D2R states, which causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such asschizophrenia,[20]autism[citation needed] andParkinson's disease.[citation needed] In order to assist in the management of these conditions, equilibration between the D2R states is controlled by implementing of agonist and antagonist D2R ligands.[citation needed] In most cases, it was observed that the problems regarding the D2R states may have genetic roots and are controlled by drug therapies.[citation needed] So far, there is no certain treatment for these mental disorders.
There is an orthosteric binding site (OBS), as well as a secondary binding pocket (SBP) on the dopamine 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D2R.[21]
It was observed that D2R exists in dimeric forms or higher order oligomers.[22] There are some experimental and molecular modeling evidences that demonstrated the D2R monomers cross link from their TM 4 and TM 5 to form dimeric conformers.[23][24]
-141C insertion/deletion[26] The polymorphisms have been investigated with respect to association withschizophrenia.[27]
Some researchers have previously associated thepolymorphism Taq 1A (rs1800497) to theDRD2 gene.However, the polymorphism resides inexon 8 of theANKK1 gene.[28] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motorfluctuations but not hallucinations in Parkinson's disease.[29][30] A splice variant in Dopamine receptor D2(rs1076560) was found to be associated with limb truncaltardive dyskinesia and diminished expression factor ofPositive and Negative Syndrome Scale (PANSS) inschizophrenia subjects.[31]
Most of the olderantipsychotic drugs such aschlorpromazine andhaloperidol are antagonists for the dopamine D2 receptor, but are, in general, very unselective, at best selective only for the "D2-like family" receptors and so binding to D2, D3 and D4, and often also to many other receptors such as those forserotonin andhistamine, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used forParkinson's disease such asbromocriptine andcabergoline are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D2 agonists, they affect other subtypes as well. Several selective D2ligands are, however, now available, and this number is likely to increase as further research progresses.
LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.[35] LSD is also a 5-HT2A agonist.
OSU-6162 – also 5-HT2A partial agonist, acts as "dopamine stabilizer"
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