title: N6-substituted adenosine receptor agonists: potential antihypertensive agents.
abstract: 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.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: B K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: C J
authors.initials: CJ
authors.lastname: Blankley
authors.forename: J A
authors.initials: JA
authors.lastname: Bristol
authors.forename: H W
authors.initials: HW
authors.lastname: Hamilton
authors.forename: W C
authors.initials: WC
authors.lastname: Patt
authors.forename: W J
authors.initials: WJ
authors.lastname: Kramer
authors.forename: S A
authors.initials: SA
authors.lastname: Johnson
authors.forename: R F
authors.initials: RF
authors.lastname: Bruns
authors.forename: D M
authors.initials: DM
authors.lastname: Cohen
authors.forename: M J
authors.initials: MJ
authors.lastname: Ryan
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D003516:Cycloparaffins; D011983:Receptors, Purinergic; D000241:Adenosine