N6-substituted adenosine receptor agonists: potential antihypertensive agents.
Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.
Trivedi
B K
BK
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Blankley
C J
CJ
Bristol
J A
JA
Hamilton
H W
HW
Patt
W C
WC
Kramer
W J
WJ
Johnson
S A
SA
Bruns
R F
RF
Cohen
D M
DM
Ryan
M J
MJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D003516:Cycloparaffins / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011918:Rats, Inbred SHR; D011983:Receptors, Purinergic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D003516:Cycloparaffins; D011983:Receptors, Purinergic; D000241:Adenosine