DRD1 - A Therapeutic Target for Idiopathic Pulmonary Fibrosis

D1 Dopamine Receptor and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is still a crippling, quickly progressing, and ultimately fatal lung disease despite ongoing therapy advancements. Over the past ten years, antifibrotic medications have been made accessible for IPF; nevertheless, their ability to improve mortality is limited, and they simply halt the disease's progression. Consequently, there is still a great need to find efficient treatment approaches for IPF. Even in the presence of TGF-β1, D1 dopamine receptor activation has antifibrotic effects. According to the findings, β2 adrenergic receptor antifibrotic signaling may be compromised by receptor suppression, and the D1 dopamine receptor is further implicated as a potential therapeutic target for IPF.

DRD1
UniProt ID	P21728
Length (aa)	446
Molecular Weight	49.3 kDa
Structure	Fig.1. Structure of DRD1.1

FDA-approved Drugs of Idiopathic Pulmonary Fibrosis

Since there is no known cure for IPF, maintaining lung function, slowing the disease's development, and enhancing the patient's general health-related quality of life are the main objectives of treatment. To slow the disease's course, there are two approved medications. An important advance in the management of IPF occurred in 2014 when the FDA authorized the antifibrotics pirfenidone and nintedanib. The capacity of both pirfenidone and nintedanib to slow down the decrease of lung function in individuals with IPF is demonstrated by their efficacy results.

DRD1 Agonism - an Effective Strategy to Reverse Fibroblast Activation

Activated fibroblasts play a crucial role in tissue fibrosis at the cellular level by promoting matrix deposition and tissue remodeling in response to profibrotic stimuli including TGF-β1 and mechanotransduction. The major regulators of fibroblast matrix deposition and proliferation have been discovered in recent work as Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) transcription co-factors. The D1 dopamine receptor was identified as a target to inactivate YAP/TAZ in lung fibroblasts by a GPCR-focused transcriptome screen. In a bleomycin lung damage model of fibrosis, the D1 receptor agonist dihydrexidine increases collagen breakdown, prevents YAP/TAZ nuclear localization, and enhances lung fibrosis resolution, all of which are consistent with the D1 receptor solely connecting to Gs. Prostaglandin E2 receptor (EP2), prostacyclin IP receptor, and relaxin family peptide receptor 1 (RXFP1) are among the other GPCRs that couple to Gs and block fibrotic signaling by elevating cAMP and interacting with downstream effector proteins, such as Exchange Factor directly Activated by cAMP1/2 (EPAC1/2) and protein kinase A (PKA). This pattern is in line with the established link between YAP/TAZ nuclear exclusion and cAMP increase. Interestingly, the decreased expression of these receptors in diseased tissue causes ligands for both the EP2 and RXFP1 receptors to lose their effectiveness in bleomycin-damaged lungs and cells originating from IPF patients.

Fig.2. Targeting the dopamine pathway.²

Creative Biolabs' Products and Services for DRD1 drug discovery

The DRD1 is a crucial regulator of reward, motor activity, and cognition in the CNS and has advantageous effects on peripheral tissues. It does this by activating Gs/Golf and promoting the synthesis of cyclic AMP (cAMP). By the signaling pathwat of DRD1, Creative Biolabs offers a wide array of DRD1 products. Our scientists are convinced that they can offer the greatest services to both domestic and foreign clients. Please contact us for more information.

References

1. Zhuang, Youwen, et al. "Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor." Cell research 31.5 (2021): 593-596.
2. Grant, Christopher E., Amy L. Flis, and Bríd M. Ryan. "Understanding the role of dopamine in cancer: past, present and future." Carcinogenesis 43.6 (2022): 517-527.