The glucose moiety of uridine 5′–diphosphoglucose is structurally permissive in activation of the human P2Y14 receptor

Abstract

The P2Y14 receptor is a signaling protein in the eight member P2Y nucleotide receptor family that is activated by UDP‐glucose (UDPG) and other uridine nucleotides. The P2Y14 receptor plays a role in the neuroimmune system, with expression in T cells, dendritic cells, and hematopoietic stem cells, and also is expressed in other tissues. We have systematically explored the structure activity relationships of UDPG analogues at this receptor. With the exception of 2‐ and 4‐thio modifications, most modifications of the nucleobase or ribose moieties diminished activity. UDPG also activates the P2Y2 receptor, but its 2‐thio analogue (MRS2690) was selective for the P2Y14 receptor and activated this receptor with 7‐fold greater potency than UDPG. Molecules in which the glucose moiety was replaced with a simple β‐methyloxy group retained agonist activity at the P2Y14 receptor. Replacement of the ribose moiety with a rigid methanocarba group, either in the North or South conformation, abolished agonist activity. Many sugar moieties, such as mannose and fructose, may be substituted for the glucose with retention of activity. Thus, the glucose moiety is the most structurally permissive region of the ligand for derivatization.