Molecular recognition in the P2Y(14) receptor: Probing the structurally permissive terminal sugar moiety of uridine-5'-diphosphoglucose.
The P2Y(14) receptor, a nucleotide signaling protein, is activated by uridine-5'-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y(14) agonist. For example, the carboxylate group of uridine-5'-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y(14) activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y(14) potency. For example, the [5'']ribose derivative had an EC(50) of 0.24muM. Selective monofluorination of the glucose moiety indicated a role for the 2''- and 6''-hydroxyl groups of 1 in receptor recognition. The beta-glucoside was twofold less potent than the native alpha-isomer, but methylene replacement of the 1''-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5'-diphosphoglucose also activates the P2Y(2) receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y(14)-selective.
Ko
Hyojin
H
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892, USA.
Das
Arijit
A
Carter
Rhonda L
RL
Fricks
Ingrid P
IP
Zhou
Yixing
Y
Ivanov
Andrei A
AA
Melman
Artem
A
Joshi
Bhalchandra V
BV
Kovác
Pavol
P
Hajduch
Jan
J
Kirk
Kenneth L
KL
Harden
T Kendall
TK
Jacobson
Kenneth A
KA
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D010738:Type C Phospholipases / Q000378:metabolism; D014500:Uracil Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014532:Uridine Diphosphate Glucose / Q000031:analogs & derivatives*
C518528:P2Y14 receptor, human; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D014500:Uracil Nucleotides; D010738:Type C Phospholipases; D014532:Uridine Diphosphate Glucose