The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Martin, Yvonne C.

doi:10.1155/2011/424535

Cited by 6 publications

(5 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). Alternatively, D1 receptor agonists produced consistent results in elevating cAMP +/-TGF-β1 with the previously identified intrinsic activities for each agonist (Grenader and Healy, 1991;Martin, 2011; McCorvy et al, 2012), being observable in cultured lung fibroblasts (Fig. 2C-D).…”

Section: Tgfβ Treatment Prevents β2-adrenergic Receptor Mediated Camp...supporting

confidence: 86%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and TGF-β1 signaling which together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors which couple to G alpha s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors which couple to G alpha s, in IPF patient-derived fibroblasts compared to non-IPF samples. Of the 14 G alpha s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-β1 signaling, with the β2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and β2 receptor agonists +/-TGF-β1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of β2 receptor agonists was lost, while D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-β1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-β1 signaling.

show abstract

Section: Tgfβ Treatment Prevents β2-adrenergic Receptor Mediated Camp...supporting

confidence: 86%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In an effort to identify a new drug target for treatment of breast cancer and bone metastasis, this study conducted a screening of drug candidates from a chemical library that consisted of 1,120 biologically active compounds. From a short list of candidates in this screening, an agonist of dopamine receptor D 1 (DRD1), A7763610, was selected for further validation.…”

mentioning

confidence: 99%

Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

Minami¹,

Liu²,

Liu³

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Dopaminergic signaling plays a critical role in the nervous system, but little is known about its potential role in breast cancer and bone metabolism. A screening of ~1,000 biologically active compounds revealed that a selective agonist of dopamine receptor D1 (DRD1), A77636, inhibited proliferation of 4T1.2 mammary tumor cells as well as MDA-MB-231 breast cancer cells. Herein, we examined the effect of A77636 on bone quality using a mouse model of bone metastasis from mammary tumor. A77636 inhibited migration of cancer cells in a DRD1-dependent fashion and suppressed development of bone-resorbing osteoclasts by downregulating NFATc1 through the elevation of phosphorylation of eIF2α. In the mouse model of bone metastasis, A77636 reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Collectively, we expect that dopaminergic signaling might provide a novel therapeutic target for breast cancer and bone metastasis.

show abstract

“…Several analogs of dihydrexidine have now been developed in the hopes of improving the pharmacokinetic profile of the parent compound. Some such analogs demonstrated greater anti-Parkinsonian activity (Martin, 2011 ; McCorvy et al, 2012 ), however none have progressed through clinical trials. Pro-drugs were also proposed to enhance lipophilicity and penetration of the blood brain barrier (Sozio et al, 2012 ).…”

Section: Signal Transduction Via the D1rmentioning

confidence: 99%

The Signaling and Pharmacology of the Dopamine D1 Receptor

Jones-Tabah

Mohammad

Paulus

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.

show abstract

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Cited by 6 publications

References 37 publications

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

The Signaling and Pharmacology of the Dopamine D1 Receptor

Contact Info

Product

Resources

About