Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

Sokoloff, Pierre; Giros, Bruno; Martres, Marie‐Pascale; Bouthenet, Marie-Louise; Schwartz, Jean‐Charles

doi:10.1038/347146a0

Cited by 2,526 publications

(1,544 citation statements)

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“…Our data indicate, however, that OPC-14597 binds with highest affinity to D 2L or D 2S receptors, and it is known that this receptor type is expressed as both autoreceptors on dopamine cells and as postsynaptic receptors on target cells (Giros et al 1989;Rao et al 1990;Snyder et al 1991). Although the involvement of D 3 receptors cannot be ruled out at present, they also do not seem to have an exclusive pre-or postsynaptic localization (Sokoloff et al 1990;Diaz et al 1995). Not enough is known of their functional properties in native tissues to allow speculation concerning their role in the unusual functional effects of OPC-14597.…”

Section: Discussioncontrasting

confidence: 63%

“…Despite this, it is unclear what molecular mechanism(s) might make a drug atypical (see Arnt and Skarsfeldt 1998). Some of the more generally accepted mechanisms include concomitant D 2 ր5-HT 2 receptor antagonist activity (Meltzer 1991) or selectivity for the D 3 or D 4 receptor (Sokoloff et al 1990;. In addition, it has been hypothesized that effective antipsychotic action may be caused by occupation of one of several types of noradrenergic receptors, although this is less well understood (Cohen and Lipinski 1986;Van Kammen et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…This strategy is based in large measure on the idea that antagonism of D 3 or D 4 receptors is necessary for antipsychotic efficacy because of the preferential distribution of these receptors in mesocorticolimbic terminal fields (Sokoloff et al 1990;Ariano et al 1997). Conversely, high affinity blockade of D 2 receptors is thought to be associated with extrapyramidal symptoms and is thus considered an undesirable property for an antipsychotic (see Joyce and Meador-Woodruff 1997).…”

Section: Cells; C-6 Cells; Schizophreniamentioning

confidence: 99%

“…The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al 1988), D 2L (Giros et al 1989;Monsma et al 1989), D 3 (Sokoloff et al 1990), and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).…”

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confidence: 99%

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Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

375

298

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cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Cells; C-6 Cells; Schizophreniamentioning

confidence: 99%

mentioning

confidence: 99%

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Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

375

298

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“…17,30 Identification of compounds that bind selectively to either the D2 or D3 dopamine receptor has been a difficult task because of this high degree of sequence homology, especially within the helical transmembrane spanning regions. 20 However, we have reported studies on the development of both D2 26,27 and D3 dopamine receptor subtype selective compounds, with varying intrinsic activity.…”

Section: ■ Discussionmentioning

confidence: 99%

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

Luedtke

Murti

Wang

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10-to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying several analogues that also exhibit D2 vs D3 dopamine receptor binding selectivity. These studies further characterize the intrinsic efficacy of the compound with the greatest binding selectivity from each chemical class, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s), using an adenylyl cyclase inhibition assay, a G-protein-coupled inward-rectifying potassium (GIRK) channel activation assay, and a cell based phospho-MAPK (pERK1/2) assay. SV 293 was found to be a neutral antagonist at D2 dopamine receptors using all three assays. SV-III-130s is a partial agonist using an adenylyl cyclase inhibition assay but an antagonist in the GIRK and phospho ERK1/2 assays. To define the molecular basis for the binding selectivity, the affinity of these two compounds was evaluated using (a) wild type human D2 and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors. Computer-assisted modeling techniques were used to dock these compounds to the human D2 and D3 dopamine receptor subtypes. It is hoped that these studies on D2 receptor selective ligands will be useful in the future design of (a) receptor selective ligands used to define the function of D2-like receptor subtypes, (b) novel pharmacotherapeutic agents, and/or (c) in vitro and in vivo imaging agents. KEYWORDS: Dopamine receptors, binding selectivity, functional selectivity, GPCR structure, D2-like dopamine receptors, GPCR model building, ligand−receptor docking T here are three dopaminergic pathways in the brain: the nigrostriatal pathway, the mesocorticolimbic pathway, and the tuberoinfundibular pathway. These pathways are involved in movement coordination, cognition, emotion, memory, reward, and regulation of prolactin secretion. Alterations in the dopaminergic pathways are thought to be involved in the pathogenesis of neurological, neuropsychiatric, and hormonal disorders. 1−6 Modulation of the dopaminergic pathways is also thought to occur as a consequence of acute or chronic abuse of pyschostimulants. 7,8 Previous studies have defined two types of dopamine receptors, the D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) receptors. D1-like receptors are linked to the activation of adenylyl cyclase via coupling to the Gs/Golf class of G proteins. 9 Stimulation of the D2-like receptors results in coupling with the Gi/Go class of G proteins, leading to the inhibition of adenylyl cyclase activity. 10,11 Agonist activation of D2-like receptors can also lead to (a) activation of G-protein-coupled inward rectifying potassium (GIRK) channels, (b) stimulation of mitogenesis, (c) an increase in...

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Pathological Gambling Caused by Drugs Used to Treat Parkinson Disease

et al. 2005

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Background: Pathological gambling is a rare potential complication related to treatment of Parkinson disease (PD). However, the etiology of this behavior is poorly understood.Objective: To examine the relationship between medical therapy for PD and pathological gambling.Methods: In our routine movement disorders practice (2002)(2003)(2004), we encountered 11 patients with idiopathic PD who had recently developed pathological gambling. We assessed the relationship to their medical therapy and compared them with cases identified by systematic review of the existing literature on pathological gambling and PD.Results: All 11 patients with PD and pathological gambling were taking therapeutic doses of a dopamine ago-nist; 3 of these patients were not treated with levodopa. In 7 patients, pathological gambling developed within 3 months of starting to take or escalating the dose of the agonist; in the other 4 with a longer latency, gambling resolved after the agonist use was discontinued. Pramipexole dihydrochloride was the agonist in 9 of 11 cases in our series and 10 of 17 in the literature (68% in total).Conclusions: Dopamine agonist therapy was associated with potentially reversible pathological gambling, and pramipexole was the medication predominantly implicated. This may relate to disproportionate stimulation of dopamine D 3 receptors, which are primarily localized to the limbic system.

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Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

Cited by 2,526 publications

References 40 publications

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

Pathological Gambling Caused by Drugs Used to Treat Parkinson Disease

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