Structure-activity relationship of (N)-Methanocarba phosphonate analogues of 5'-AMP as cardioprotective agents acting through a cardiac P2X receptor.
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 P2Y(1) 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 CH(3)-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.
Kumar
T Santhosh
TS
Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-0810, USA.
Zhou
Si-Yuan
SY
Joshi
Bhalchandra V
BV
Balasubramanian
Ramachandran
R
Yang
Tiehong
T
Liang
Bruce T
BT
Jacobson
Kenneth A
KA
D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007260:Infusion Pumps; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D063065:Organophosphonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D013329:Structure-Activity Relationship
C549056:4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo(3.1.0)hexane; C549057:4-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonoethenyl)-bicyclo(3.1.0)hexane; D002316:Cardiotonic Agents; C549055:MRS 2339; D063065:Organophosphonates; C546382:P2RY1 protein, human; C546383:P2ry1 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D000249:Adenosine Monophosphate; D002118:Calcium