Novel dopamine receptors half a decade later

doi:10.1016/S0165-6147(00)89044-6

Trends in Pharmacological Sciences

Volume 16, Issue 8, August 1995, Pages 270-275

https://doi.org/10.1016/S0165-6147(00)89044-6 Get rights and content

Abstract

Only half a decade ago, the effects of dopamine were all attributed to activation of two receptor subtypes, the D₁ and D₂, with opposing effects on adenylate cyclase, and for which apparently selective ligands were available. From the end of 1988, however, the application of homology cloning techniques starting from sequences of the seven transmembrane domain catecholamine receptors, particularly that of the D₂ receptor, led to the identification of ‘novel’, previously uncharacterized dopamine receptors. In this article, Pierre Sokoloff and Jean-Charles Schwartz discuss the functional significance of such diversity, as well as the new therapeutic perspectives it offers.

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Dopamine receptors can play either excitatory or inhibitory roles in the nervous system. These receptors include two major groups, the D1-class (D1 and D5) and D2-class (D2, D3 and D4) receptors (Sokoloff and Schwartz, 1995). Normally, D1-class receptor mediate excitatory or inhibitory response, whereas D2-class receptors mediate an inhibitory response (Romanelli et al., 2010).
A neuromodulatory role for dopamine has been reported for magnocellular neuroendocrine cells in the mammalian hypothalamus. We examined its potential role as a local intercellular messenger in the neuroendocrine Dahlgren cell population of the caudal neurosecretory system (CNSS) of the euryhaline flounder Paralichthys olivaceus. In vitro application of dopamine (DA) caused an increase in electrical activity (firing frequency, recorded extracellularly) of Dahlgren cells, recruitment of previously silent cells, together with a greater proportion of cells showing phasic (irregular) activity. The dopamine precursor, levodopa (L-DOPA), also increased firing frequency, cell recruitment and enhanced bursting and tonic activity. The effect of dopamine was blocked by the D1, D5 receptor antagonist SCH23390, but not by the D2, D3, D4 receptor antagonist amisulpride. Transcriptome sequencing revealed that all DA receptors (D1, D2, D3, D4, and D5) were present in the flounder CNSS. However, quantitative RT-PCR revealed that D5 receptor mRNA expression was significantly increased in the CNSS following dopamine superfusion. These findings suggest that dopamine may modulate CNSS activity in vivo, and therefore neurosecretory output, through D5 receptors.
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Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the D₂R and D₃R subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing D₂R- or D₃R-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the D₂R or D₃R in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics.
Role of dopamine D<inf>4</inf> receptors in copulatory behavior: Studies with selective D<inf>4</inf> agonists and antagonists in male rats
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Dopamine influences the anticipatory and consummatory phases of sexual behavior, by acting on receptors of the D2 family (D₂, D₃ and D₄) and in particular of the D₂ subtype, although evidence for a role of D₄ receptors in erectile function and copulatory behavior is also available. In order to clarify such a role of D₄ receptors, the effect of selective D₄ receptor agonists and antagonists on copulatory behavior of sexually potent male rats in classic copulation tests with a receptive female, was compared with that of apomorphine and haloperidol, a classic dopamine receptor agonist and antagonist, respectively. PD-168,077 (0.05–0.2 mg/kg) and ABT-724 (0.01–0.04 mg/kg), two selective D₄ receptor agonists, given subcutaneously, improved dose-dependently copulatory behavior as shown by the decrease of mount frequency and post ejaculatory interval induced by PD-168,077, and of mount frequency, ejaculation latency, post ejaculatory and inter intromission intervals induced by ABT-724, and by the increase of ejaculation frequency and copulatory efficacy induced by both drugs. Conversely, L-745,870 (1–5 mg/kg), a selective D₄ receptor antagonist, given intraperitoneally, impaired dose-dependently copulatory behavior, as shown by the increase in intromission and ejaculation latencies, mount frequency, post ejaculatory interval and the decrease in ejaculation frequency and copulatory efficacy induced by this drug. L-745,870 (5 mg/kg) administered before PD-168,077 (0.2 mg/kg) or ABT-724 (0.04 mg/kg), also abolished completely the facilitatory effects of both PD-168,077 and ABT-724 on sexual behavior. These results confirm the involvement of D₄ receptors in specific aspects of male rat copulatory behavior that overlap only partially with those influenced by apomorphine and haloperidol.
Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding
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Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpiperazine head group by an aminoindane moiety was investigated resulting in dopamine D₃ receptor antagonists and agonists with K_i values in the sub- and low-nanomolar range. As a potentially irreversible ligand, the 3,4,5-trifluoro-substituted phenylazocarboxamide 7 was investigated for its N-arylating properties by incubation with the protected lysine analog 18 and with the L89K mutant of the dopamine D₃ receptor. Whereas covalent bond formation with the lysine unit in TM2 of D₃ could not be detected, substantial N-arylation of the side chain of the model compound 18 has been observed.
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Citation Excerpt :
They are similar in structures with seven transmembrane helixes domain (TM helix I–VII), extracellular loops (ECL) and intracellular loops (ICL). There are five different receptor subtypes of DA receptors which could be divided into two families, D1-like (D1 and D5 subtypes) and D2-like (D2, D3 and D4 subtypes) [37–42]. The mental disorder diseases, such as schizophrenia, major depression and bipolar disorder, are associated with D2-like receptors [43].
Psychiatric disorders, such as schizophrenia, bipolar disorder and major depression, are paid more and more attention by human due to their upward tendency in modern society. D₂-like and 5-HT_2A receptors have been proposed as targets of antipsychotic drugs. Atypical antipsychotic drugs have been deemed to improve the treatment of positive, negative and extrapyramidal symptoms. Unfortunately, no experimental structures for these receptors are available except D₃ receptor (D₃R). Therefore, it is necessary to construct structures of D₂-like and 5-HT_2A receptors to investigate the interaction between these receptors and their antagonists. Accordingly, homology models of dopamine D₂, D₃, D₄ and serotonin 5-HT_2A receptors have been built on the high-resolution crystal structure of the β₂-adrenergic receptor, and refined by molecular dynamics simulations. The backbone root-mean-square deviation (RMSD) of D₃R model relative to crystal structure is 1.3 Å, which proves the reliability of homology modeling. Docking studies reveal that the binding modes of four homology models and their antagonists are consistent with experimental site-directed mutagenesis data. The calculated pK_i values agree well with the experimental pK_i ones. Antagonists with linear structures such as butyrophenones and benzisoxazolyl piperidines are easily docked into D₂-like and 5-HT_2A receptors. Polycyclic aromatic compounds have weaker affinity with four receptors. Homology models of D₂-like and 5-HT_2A receptors will be helpful for predicting the affinity of novel ligands, and could be used as three-dimensional (3D) templates for antipsychotic virtual screening and further drug discovery.
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A series of fluoro substituted pyridinylcarboxamides and their phenylazo analogues with high affinity and selectivity for the dopamine D3 receptor was synthesized by the use of 6-fluoropyridine-3-carbonyl chloride (1) and fluorophenylazocarboxylic ester (2). Several of these compounds (9a–e and 10a–h) have been evaluated in vitro, among which 9b, 10a, 10c and 10d proved to have at least single-digit nanomolar affinity for D3. They also exhibit considerable selectivity over the other dopamine receptor subtypes and noteworthy selectivity over the structurally related serotonin receptor subtypes 5-HT_1A and 5-HT₂, offering potential radiotracers for positron emission tomography.

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Trends in Pharmacological Sciences

ReviewNovel dopamine receptors half a decade later

Abstract

J. Biol. Chem.

Eur. J. Pharmacol.-Mol. Pharmacol. Sect.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Brain Res.

Neuroscience

Mol. Brain Res.

Neurosci. Lett.

Trends Neurosci.

Eur. J. Pharmacol.-Mol. Pharmacol. Sect.

Trends Pharmacol. Sci.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Mol. Pharmacol.

J. Pharmacol. Exp. Ther.

Nature

J. Neurosci.

Mol. Endocrinol.

Mol. Pharmacol.

Review
Novel dopamine receptors half a decade later