CRTH2 (GPR44)

Prostaglandin D2 receptor 2 (DP2, CRTH2, GPR44) is a human protein encoded by the PTGDR2 gene. DP2 has recently been found when activated by elevated level of prostaglandin D2 (PGD2), it could inhibit hair growth. This suggests the DP2 pathway as a potential target for bald treatment.

1027847-67-1
AMG-009
1027847-67-1
1093108-50-9
BI671800
1093108-50-9
1169483-24-2
Vidupiprant
1169483-24-2
1218918-62-7
MK-7246
1218918-62-7
629645-40-5
AZ11665362
629645-40-5
802904-66-1
AZD1981
802904-66-1
B0084-474875
Setipiprant
866460-33-5
PGD2-IN-1
885066-67-1

Background


Prostaglandin D2 receptor (DP2 Receptors), also termed CRTH2 (Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells), is a kind of G-protein-coupled receptors and a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. It belongs to a human protein encoded by the PTGDR2 gene and GPR44. CRTH2 has also been designated as a cluster of differentiation 294 (CD294). CRTH2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). CRTH2 is a heterogeneous guanosine triphosphate binding protein complex. It has three N-glycosylation sites (Asn-10, Asn-90 and Asn-297), two protein kinase phosphorylation sites (Ser-50, Thr-145) and Hydroxyl-terminal 6 phosphorylation sites (5 serine residues, 1 threonine residue). When CRTH2 binds to prostaglandin D2, it can cause the receptor to change shape and bind to the intracellular inactive state of the G-protein. This binding causes G-protein to abandon guanosine diphosphate (GDP) and accept guanosine triphosphate (GTP). GTP deforms a small loop of the G-protein that is broken down into two parts. The GTP-carrying subunit moves along the membrane until adenylyl cyclase is encountered, and the small cyclic structure binds to adenylyl cyclase, which promotes the activation of downstream adenylate cyclase, and then in adenosine. Acid cyclase catalyzes the conversion of intracellular adenosine triphosphate (ATP) to the second messenger cAMP and triggers the biological effects of the target cells. GPR44 is widely distributed in the endocrine, reproductive, digestive, respiratory, cardiovascular, urinary and nervous systems and is expressed in a variety of inflammatory cells, such as eosinophils, lymphocytes, and mast cells. Although widely distributed, notably in the gastrointestinal tract, the focus has been almost exclusively on leukocytes.

PGD2 activates CRTH2 and promotes the production of eosinophils, basophils, and Th2 lymphocyte chemotaxis, causing lymphocytes to accumulate at the site of the antigen's excitons and producing a series of allergic reactions. In addition, CRTH2 and DP receptors are also present on the surface of mast cells and Th2 cells, and Th2 cells generate a large number of cytokines when activated by PGD2. These cytokines can drive the maturation of T cells by inducing the expression of macrophage-derived cytokines. CRTH2 is expected to become new targets for overcoming allergic reactions. The CRTH2 inhibitors used for the treatment of asthma mainly include selective inhibition of ramatroban, 4-aminoquinolone derivatives, and phthalic acid derivatives. At present, there is no real prostanoid asthma treatment, but there are already some non-PG selective inhibitors of asthma that are used for clinical trials such as ZD-1981, ACT-129968, OC-459, AMG-853, AP-761, AZD-5985, AZD-8075, and AM-211.Their chemical structures are shown in Fig. 1.

Chemical-structures-of-some-CRTH2-inhibitors

Fig. 1. Chemical structures of some CRTH2 inhibitors

Besides, PGD2 is an important inflammatory mediator. It can activate NF-κB, induce the up-regulation of cyclooxygenase-2 (COX-2), and induce eosinophils to synthesize leukotrienes and other inflammatory mediators. Activation of CRTH2 by PGD2 causes eosinophilic, basophilic cell degeneration, chemotaxis, and degranulation, and promotes the release of interleukin, migration of dendritic cells, and degranulation of mast cells by Th2 cells, leading to an inflammatory response. The role of DP in some inflammations is the opposite of CRTH2. For example, reducing the number of eosinophils and inhibiting the migration of dendritic cells, although the affinity of these two receptors for PGD2 is comparable, the CRTH2-mediated inflammatory signal is stronger than the DP-mediated inhibitory signal probably due to the low level of expression of DP in the body.

Reference

Sidharta, P.N., Diamant, Z., Dingemanse, J. (2014). Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects". Fundamental & Clinical Pharmacology. 28 (6): 690–699.