1215320-13-0Relevant articles and documents
Molecular recognition in the P2Y14 receptor: Probing the structurally permissive terminal sugar moiety of uridine-5′-diphosphoglucose
Ko, Hyojin,Das, Arijit,Carter, Rhonda L.,Fricks, Ingrid P.,Zhou, Yixing,Ivanov, Andrei A.,Melman, Artem,Joshi, Bhalchandra V.,Kovac, Pavol,Hajduch, Jan,Kirk, Kenneth L.,Harden, T. Kendall,Jacobson, Kenneth A.
, p. 5298 - 5311 (2009)
The P2Y14 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 P2Y14 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 P2Y14 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 P2Y14 potency. For example, the [5′′]ribose derivative had an EC50 of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2′′- and 6′′-hydroxyl groups of 1 in receptor recognition. The β-glucoside was twofold less potent than the native α-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 P2Y2 receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y14-selective.
Structure-activity relationship of (N)-methanocarba phosphonate analogues of 5′-AMP as cardioprotective agents acting through a cardiac P2X receptor
Santhosh Kumar,Zhou, Si-Yuan,Joshi, Bhalchandra V.,Balasubramanian, Ramachandran,Yang, Tiehong,Liang, Bruce T.,Jacobson, Kenneth A.
experimental part, p. 2562 - 2576 (2010/08/19)
P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y1 receptor). Two phosphonates,(1′S,2′R,3′S,4′R,5′S)- 4′-(6-amino-2-chloropurin-9-yl)-2′,3′-(dihydroxy) -1′-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5′-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5′-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.
