Dopamine D1 receptor ligands: Where are we now and where are we going

  title={Dopamine D1 receptor ligands: Where are we now and where are we going},
  author={Jing Zhang and Bing Xiong and Xuechu Zhen and Ao Zhang},
  journal={Medicinal Research Reviews},
The dopamine (DA) D1 receptor is the most highly expressed DA receptor subtype among the DA receptor family. Although the first DA D1 receptor selective ligand SCH‐23390 (1) was introduced more than two decades ago, clinically useful D1 receptor selective ligands are rare. A renewed interest was ignited in the early 1990s by Nichols and Mailman who developed dihydrexidine (27a), the first high affinity full efficacy agonist for the D1 receptor. Since then, a number of D1 receptor agonists with… 

Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics.

The major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators are reviewed, highlighting their structure-activity relationships and medicinal chemistry.

Ligand recognition and biased agonism of the D1 dopamine receptor

Cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207 show that the broad conformation stabilized by two fen oldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.

Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor

A novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties are reported, and the molecular basis for catechol-specific recruitment of β-arrestin to D1Rs is defined.

Synthesis and Characterization of D1 Dopamine Receptor Positive Allosteric Modulators

  • Biology, Psychology
  • 2021
This project aims to synthesize thiophene-based D1R PAMs targeting a novel D 1R allosteric site, screen for receptor selectivity, and optimize potentiation, and provides critical guidance to future D1 PAM drug discovery, which will explore substitutions on the cyclohexane and pyridine occupies a different allosterics site on the D1 R.

Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation.

This review highlights the recent progress in the field, covering both orthosteric and allosteric modes of activation, discusses the elucidation of theAllosteric binding sites, and summarizes the clinical development status of various compounds.

A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods

This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands.

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D1 Receptor Catechol Agonists

The hypothesis that the decreased D1 activity of chroman analogs results from a ligand intramolecular hydrogen bond that impairs the ability of the catechol to engage the receptor is supported.

D1-like receptors distinguishing thieno-azecine regioisomers

Thorough analysis of the amino acid residues constituting the binding pockets of the target dopamine receptor subtypes revealed that at the D5 receptor, either serine S 6.62 and threonine T 7.33 residues or a water network, stabilized by anionic amino acids could contribute to the selectivity pattern of the synthesized compounds.

Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes




Dihydrexidine--the first full dopamine D1 receptor agonist.

An updated overview of the pharmacology of dihydrexidine is provided and possible clinical utility of dopamine D(1) receptor agonists in various central nervous system disorders is discussed.

Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum

The hypothesis that the antiparkinsonian effect of dopamine receptor agonists is mediated by a more complex interactions with dopamine receptor subtypes than currently believed is supported.

Parkinson's disease and D1 dopamine receptors.

The role of the D1-like dopamine receptors in Parkinson's disease (PD) is reviewed, an idea supported by the location of D1 receptors in key aspects of basal ganglia circuitry, and scientific advances have suggested that therapeutic profiles may be improved.

Recent advances towards the discovery of dopamine receptor ligands

This review provides an overview of the recent patent literature during 2003 – 2005 on the development of therapeutic agents, mainly targeting the five dopamine receptors.

Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist.

The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy- 5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine), the first high-potency, full

Dopamine receptors: from structure to function.

Target deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions and provide unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders.

SCH 23390: the first selective dopamine D1-like receptor antagonist.

  • J. Bourne
  • Biology, Psychology
    CNS drug reviews
  • 2001
Previous in vivo pharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman, providing evidence of the potential importance of D1-like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures.

Spare receptors and intrinsic activity: Studies with D1 dopamine receptor agonists

The intrinsic activities of selected dopamine D1 receptor agonists were compared in three distinct molecular expression systems, C‐6, Ltk, and GH4, cells transfected with primate D1A receptors, demonstrating significant and biologically meaningful differences in intrinsic efficacy.