Structure-activity relationships of adenosines with heterocyclic N6-substituents.

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Ashton TD, Aumann KM, Baker SP, Schiesser CH, Scammells PJ

Structure-activity relationships of adenosines with heterocyclic N6-substituents.

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6779-84. Epub 2007 Oct 17.

PubMed ID

17967536 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tecadenoson	Adenosine receptor A1	Ki (nM)	65	N/A	N/A	Details
Tecadenoson	Adenosine receptor A1	IC 50 (nM)	8.2	N/A	N/A	Details