# Dopamine receptor D3

Dopamine receptor D$_3$ is a protein that in humans is encoded by the DRD3 gene.
This gene encodes the D$_3$ subtype of the dopamine receptor. The D$_3$ subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that this receptor plays a role in cognitive and emotional functions. It is a target for drugs which treat schizophrenia, drug addiction, and Parkinson's disease. Alternative splicing of this gene results in multiple transcript variants that would encode different isoforms, although some variants may be subject to nonsense-mediated decay (NMD). On a side note, it is also the Dopamine Receptor sub-type possessing the highest binding affinity for Dopamine itself and may explain why non-ergoline Dopamine Agonists are D$_3$-preffering

## Function

Alpha-synuclein (α-Syn) aggregation via Lewy bodies inclusion, a pathogenic signature exclusively present in PD patients, is decreased by D3 agonists while DA content is elevated by inhibiting DA reuptake and breakdown. The regulation of α-Syn aggregation and clearance enhances brain-derived neurotrophic factor (BDNF) secretion, which ultimately ameliorates neuroinflammation and oxidative stress while promoting neurogenesis and interacting with other DA receptors.
D$_3$ agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression. Apomorphine has the ability to help PD patients with their cognition awareness. In addition to having antidepressant properties such as regulating the depression-like behaviors and depression development, pramipexole has the capability to prevent and slow down cell apoptosis as well as to restore damaged neural networks and connections while rotigotine help PD patients to attenuates hyperpyrexia syndrome and schizophrenia.

## Animal studies

D$_3$ agonists have been shown to disrupt prepulse inhibition of startle (PPI), a cross-species measure that recapitulates deficits in sensorimotor gating in neuropsychiatric disorders such as schizophrenia. In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.

## Ligands
### Agonists

* trans-N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D$_4$, D$_2$, 5-HT$_{1A}$, and α1-receptors
* (-)-7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol
* 5-OH-DPAT
* 7-OH-DPAT
* Pergolide
* 8-OH-PBZI (cis-8-Hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz[e]indole)
* Apomorphine (non-selective dopamine agonist)
* Bromocriptine (non-selective dopamine agonist)
* Captodiame
* Aripiprazole (non-selective full agonist)
* CJ-1639
* compound R,R-16: 250x binding selectivity over D$_2$
* Dopamine (endogenous agonist)
* ES609
* FAUC 54
* FAUC 73
* PD-128,907
* PF-219,061 (extremely selective)
* PF-592,379
* Piribedil (non-selective dopamine agonist)
* Pramipexole (non-selective dopamine agonist)
* Quinelorane (also D$_2$ agonist)
* Quinpirole (also D$_2$ agonist)
* Ropinirole (non-selective dopamine agonist)
* Rotigotine (non-selective dopamine agonist)

### Partial agonists

* BP-897
* Brexpiprazole (non-selective)
* Buspirone (non-selective)
* Cariprazine
* CJB 090
* CJ-1037 (extremely selective)
* FAUC 460 (highly selective)
* FAUC 346 (highly selective)
* Pardoprunox (non-selective)
* Roxindole (possibly a partial agonist at the D$_3$ autoreceptors, non-selective)
* OS-3-106
* UH-232
* WW-III-55

### Antagonists

* Most Antipsychotics
* Amisulpride (non-selective)
* Buspirone
* Cyproheptadine (non-selective)
* PG 01037
* Domperidone (peripheral D$_2$ and D$_3$ antagonist)
* FAUC 365, silent antagonist, subtype selective
* GR-103,691
* GSK-598809 (highly selective)
* Haloperidol (non-selective, blocks all dopamine receptor subtypes, though D$_3$ with the strongest affinity)
* N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides
* Mesdopetam
* Nafadotride
* NGB-2904
* PNU-99,194 (moderately selective over D$_2$)
* Raclopride (also D$_2$ antagonist)
* S-14,297 (selective)
* S33084
* SB-277011-A, selective D$_3$ antagonist, 80x selectivity over D$_2$ with no partial agonist effects, used in drug addiction research as a potential therapy for addiction to several different drugs
* SR 21502 (highly selective)
* Sulpiride (also D$_2$ antagonist)
* U99194
* YQA14 (high affinity and selectivity)
* Risperidone

### Allosteric modulators

* SB269652

## Interactions

Dopamine receptor D$_3$ has been shown to interact with CLIC6 and EPB41L1.
DRD3 Ser9Gly polymorphism(rs6280), which is a single nucleotide polymorphism (SNP) with variant base C/T is linked to variation in PD such as depression severity, impulse control disorders, behavioral addiction and aberrant decision-making.