Design of (N)-methanocarba adenosine 5'-uronamides as species-independent A3 receptor-selective agonists.

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Melman A, Gao ZG, Kumar D, Wan TC, Gizewski E, Auchampach JA, Jacobson KA

Design of (N)-methanocarba adenosine 5'-uronamides as species-independent A3 receptor-selective agonists.

Bioorg Med Chem Lett. 2008 May 1;18(9):2813-9. doi: 10.1016/j.bmcl.2008.04.001. Epub 2008 Apr 4.

PubMed ID

18424135 [ View in PubMed

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Abstract

2-Chloro-5'-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A(3) adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A(1)AR. Therefore, we varied substituents at the N(6) and C2 positions in search of compounds that have improved A(3)AR selectivity and are species independent. An N(6)-methyl analogue was balanced in affinity at mouse A(1)/A(3)ARs, with high selectivity in comparison to the A(2A)AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A(3)AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A(3)AR selectivity more effectively than similar chains attached at the 3-position of the N(6)-benzyl group.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Piclidenoson	Adenosine receptor A3	Ki (nM)	1.74	N/A	N/A	Details