Dopamine Receptors

Dopamine receptors were initially differentiated into two major types based on the ability of dopamine to stimulate (D₁) or inhibit (D₂) adenylyl cyclase activity and produce the second-messenger molecule cyclic-AMP (cAMP). Extraordinary advances in molecular genetics have greatly facilitated the isolation and characterization of novel dopamine receptors, D₃, D₄ and D₅, with different anatomical localization from traditional D₁ or D₂ receptors. Based upon their peptide sequences, pharmacological profiles, including their effects on different signal transduction cascades, the five dopamine receptors are currently divided into two families; the D₁-like family, which includes D₁ and D₅ receptors, and the D₂-like family, which includes D₂, D₃ and D₄ receptors. The dopamine receptors are coupled to G-proteins and modified by attached carbohydrate, lipid-ester or phosphate groups. They are characterized by having seven hydrophobic transmembrane-spanning regions, as well as a functionally third intracytoplasmic loop that interacts with G-proteins and other effector molecules to mediate the physiological and neurochemical effects of the receptors.

Dopamine D₁ and D₂ receptors are widely expressed in forebrain regions and occur in tissues at sufficiently high concentrations so that they can be studied in situ. Other receptors (D₃, D₄ and D₅) have more limited distribution and occur at such low concentrations that experimental investigation of the receptors in situ is more difficult. These latter receptors and their proposed effector mechanisms have been studied subsequent to their expression in genetically transfected cell lines, but care must be taken in extrapolating the results obtained with the cloned receptor to the in vivo situation.

Identification of compounds that discriminate between D₁-like and D₂-like receptors strongly supports division of the dopamine receptors into two families. However, most drugs and candidate ligands bind with high affinity to more than one dopamine receptor subtype to hinder comprehensive pharmacological and neurobiological characterization of each dopamine subtype. No agents have been identified that are selective for D₁ versus D₅ receptors, for example, and most compounds targeting D₂-like receptors have substantial affinity for more than one member of the family.

Mice with targeted gene depletion of specific dopamine receptor subtypes have been developed using recombinant DNA technologies with embryonic stem cells. Such gene "knock-out" mutant mice provide valuable models for studies of physiological and behavioral effects of dopamine receptors. However, such findings should be interpreted carefully since phenotypic variability, genetic background, and complex compensatory developmental adaptations may influence outcomes due to factors other than the absence of specific dopamine receptor genes. Advancing research on dopaminergic systems requires empirical searching for improved, more selective, novel ligands for dopamine receptor subtypes, guided by better understanding of the molecular, cellular, and behavioral physiology and neuropharmacology of this important class of cerebral receptors.

Illnesses for which dopamine receptor agonists or antagonists are clinically useful are common, usually chronic, and their current treatments are imperfectly palliative and limited by adverse-effects. Dopamine D₁ and D₂ agonists are effective in improving symptoms of Parkinsons disease (PD). Antagonistic activity at D₂ receptors remains an essential component in the pharmacological profiles of standard and newer antipsychotic drugs developed for treatment of schizophrenia and other idiopathic psychotic disorders. D₃ receptor ligands showed evidence of antagonizing reinforcing behaviors of cocaine and alleviating levodopa-induced dyskinesia in patients with PD. Preclinical studies are encouraging the development of dopamine D₄-selective compounds for treatment of attention-deficit hyperactivity disorder and other conditions that commonly involve attentional and cognitive dysfunctions. In addition, these agents are being considered as potential novel treatments for erectile dysfunction. The recent evidence, which indicates that D₅ receptors play a pivotal role in blood pressure regulation, suggests that D₅-selective compounds, once developed, may prove useful for treatment of hypertension. All these circumstances continue to make dopamine receptors attractive pharmacotherapeutic targets for improved treatment of neuropsychiatric and other disorders.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Currently Accepted Name	D1	D2	D3(rat) (D181) D3 (human)
Structural Information	446 aa (human)	short: 414 aa (human)a long: 443 aa (human)a	400 aa (human)
Subtype Selective Agonists	R(+)-SKF-38393 (S101) A-68930 (A8852) A-86929 A-77636 (A255) Fenoldopam (F6800) Dihydrexidine	U-91,356A TNPA (D030)	PD 128,907 (P216) R(+)-7-OH-DPAT (H168) BP 897
Subtype Selective Antagonists	R(+)-SCH-23390 (D054) SCH-39166	L-741,626 (L135)	S(– )-Nafadotride GR 103,691 (G0544) SB 277011-A (S4326) U 99194A (U116) KCH-1110
Signal Transduction Mechanisms	Gs, Golf (increase cAMP) Gq (activate PLC) ↑ L-type Ca2+ channel ↓ K+ currents	Gi/o (decrease cAMP) Gi/q (increase IP3/DAG) ↑ arachadonic acid release ↓ Na+ currents	Gi/o (decrease cAMP) ↑ K+ currents
Radioligands of Choice	[3H]-SCH-23390 [125I]-SCH-23982	[3H]-Nemonapride [3H]-Spiperone [3H]-Raclopride	[3H]-7-OH-DPAT [125I]-7-OH-PIPAT
Brain Tissue Expression	Basal ganglia, olfactory tubercle, cerebral cortex	Basal ganglia, olfactory tubercle, anterior pituitary	Islands of calleja, shell of accumbens, cerebellum
Disease Relevance	Parkinson's disease, Tourette's syndrome, Huntington's chorea	Schizophrenia, Parkinson's disease	Drug abuse, schizophrenia, erectile dysfunction

Currently Accepted Name	D4	D5
Structural Information	386 aa (rat)b	477 aa (human)
Subtype Selective Agonists	PD 168,077 (P233) CP-226,269 A-369508 ABT-724 (A5111)	R(+)-SKF-38393 (S101) A-68930 (A8852)
Subtype Selective Antagonists	CP-293,019 L-745,870 (L131) L-750,667 (L133) RBI-257 U-101,387 A-381393	R(+)-SCH-23390 (D054) SCH-39166
Signal Transduction Mechanisms	Gi, Gz (decrease cAMP) ↑  arachadonic acid release ↑ phospholipid methylation ↓ L-type Ca2+ channel	Gs (increase cAMP) ↑ L-type Ca2+ channel
Radioligands of Choice	[3H]-Nemonapride [3H]-Spiperone [3H]- A-369508	[3H]-SCH-23390 [125I]-SCH-23982
Brain Tissue Expression	Cerebral cortex, hippocampus, thalamus	Hippocampus, basal ganglia, cerebellum
Disease Relevance	ADHD	Hypertension

Footnotes

a) Deduced aa composition of putative third cytoplasmic loop differs between short and long isoforms.

b) Deduced aa composition of putative third cytoplasmic loop varies due to the presence of 40 base pair repeats. The number of repeats is sometimes indicated (e.g., D4.2 for two repeats).

Abbreviations

A-369508: 2-[4-(2-Cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide
A-381393: 2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H-benzoimidazole
A-68930: 1R,3S-1-Aminomethyl-5,6-dihydroxy-3-phenylisochroman hydrochloride
A-77636: (–)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran
A-86929: (–)-trans-9,10-Hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride
ABT-724: 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole
BP 897: N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide
CP-226,269: 5-Fluoro-2-[[4-2(2-pyridinyl)-1-piperazinyl]methyl]-1H-indole
CP-293,019: 7-[(4-Fluorophenoxy)methyl]-2-(5-fluoro-2-pyrimidinyl)octahydro-(7R,9aS)-2H-pyrido[1,2-a]pyrazine
GR 103,691: {4'-Acetyl-N-{4-[(2-methoxy-phenyl)-piperazin-1-yl]-butyl}-biphenyl-4-carboxamide
KCH-1110: 1-(2-Ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine
L-741,626: (±)-3-[4-(4-Chlorophenyl)-4-hydroxypiperidinyl]-methylindole
L-745,870: 3-([4-(4-Chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo(2,3-b)pyridine
L-750,667: (±)-3-[4-Iodophenyl)-1-piperazyl]methylpyrrolo[2,3-b]pyrimidine
7-OH-DPAT: 2-Dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene
R(+)-7-OH-DPAT: R(+)-2-Dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene
7-OH-PIPAT: (+)-7-Hydroxy-2-(N-n-propyl-N-3′-iodo-2-propenyl)aminotetralin
PD 128,907: 3,4,4a,10b-Tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol
PD 168,077: N-[[4-(2-Cyanophenyl)-1-piperazinyl]methyl]-3-methyl-benzamide
RBI-257: 1-[4-Iodobenzyl]-4-[[2-[3-isopropoxy]pyridyl]-methylamino]piperidine
SB 277011-A: trans-N-[4-[2-(6-Cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide
SCH-23390: 7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
SCH-39166: (–)-trans-6,7,7a,8,9,13b-Exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-naphto-[2,1b]-azepine hydrochloride
TNPA: R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide
R(+)-SKF-38393: 1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol
U-101,387: 4-[4-[2-[(1S)-3,4-Dihydro-1H-2-benzopyran-1-yl]ethyl]-1-piperazinyl]-benzenesulfonamide
U-91,356A: (R)-5,6-Dihydro-5-(propylamino)-4H-imidazo[4,5,1-ij]quinolin-2-(1H)-one monohydrochloride
U99194A: 5,6-Dimethoxy-2-(N-dipropyl)-aminoindan

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