Structure-activity relationships of adenosines with heterocyclic N6-substituents.
Two series of N(6)-substituted adenosines with monocyclic and bicyclic N(6) substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([(3)H]CPX), potency, and intrinsic activity (cAMP accumulation) at the A(1) adenosine receptor in DDT(1) MF-2 cells. In the monocyclic series, the N(6)-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N(6)-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the A(1)AR; IC(50)=3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N(6)-position was explored. N(6)-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (38) proved to be a reasonably potent A(1) agonist (K(i)=51 nM, IC(50)=35 nM) while further substitution on the 7''-nitrogen with tert-butoxycarbonyl (31, IC(50)=2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC(50)=9.0 nM) gave highly potent A(1)AR agonists.
Ashton
T D
TD
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.
Aumann
Kylee M
KM
Baker
Stephen P
SP
Schiesser
Carl H
CH
Scammells
Peter J
PJ
D000241:Adenosine / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D058906:Purinergic P1 Receptor Agonists; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D058906:Purinergic P1 Receptor Agonists; D000241:Adenosine