Synthesis and biological evaluation of adenosines with heterobicyclic and polycyclic N(6)-substituents as adenosine A(1) receptor agonists.
A concise synthesis of a series of N(6)-substituted adenosines with bicyclo[3.2.1]octan-6-yl and polycyclic N(6)-substituents has been developed. The adenosine A(1) receptor (A(1)R) affinity and potency of these compounds was initially assessed using competitive binding assays and cyclic adenosine monophosphate (cAMP) accumulation assays in DDT(1) MF-2 cells. The potency and receptor subtype selectivity of selected examples was further evaluated by measuring their effects on cAMP accumulation at all human adenosine receptor subtypes expressed in CHO cells. The results of these assays indicated that all of the synthesised N(6)-substituted adenosines are full agonists at A(1) R and activate this receptor selectively over the other adenosine receptor subtypes. The two standout compounds in terms of potency were N(6)-(3-thiabicyclo[3.2.1]octan-6-yl)adenosine and N(6)-(cubanylmethyl)adenosine with EC(50) values at human A(1)R of 2.3 nM and 1.1 nM, respectively. The cubanylmethyl derivative in particular proved to be highly receptor subtype selective. These two compounds were further evaluated in a simulated ischaemia model in cultured cardiomyoblasts, where they were found to impart protective effects under hypoxic conditions that resulted in a significant reduction in cell death.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Joshua I
JI
Gosling
Stephen P
SP
Baker
John M
JM
Haynes
Michael
M
Kassiou
Colin W
CW
Pouton
Lyndon
L
Warfe
Paul J
PJ
White
Peter J
PJ
Scammells
D000241:Adenosine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D058907:Adenosine A1 Receptor Agonists; D011084:Polycyclic Aromatic Hydrocarbons; D043682:Receptor, Adenosine A1; D000241:Adenosine