Synthesis and structure-activity relationships of 2-hydrazinyladenosine derivatives as A(2A) adenosine receptor ligands.

Article Details

Citation

Copy to clipboard

El-Tayeb A, Gollos S

Synthesis and structure-activity relationships of 2-hydrazinyladenosine derivatives as A(2A) adenosine receptor ligands.

Bioorg Med Chem. 2013 Jan 15;21(2):436-47. doi: 10.1016/j.bmc.2012.11.021. Epub 2012 Nov 27.

PubMed ID

23245803 [ View in PubMed

]

Abstract

A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A(2A)AR selective agonists and to explore the structure-activity relationships of this class of compounds at A(2A)AR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A(2A)AR affinity and very high selectivity toward A(2A)AR. The most potent bis-sugar nucleoside was obtained with the D-galactose derivative 16 which exhibited a K(i) value of 329 nM at A(2A)AR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10-14 were found to have low nanomolar affinity for A(2A)AR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with K(i) values of 16.1, 24.4, and 12.0 nM, respectively, at rat A(2A)AR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A(2A)AR.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Binodenoson	Adenosine receptor A2a	Ki (nM)	270	N/A	N/A	Details
Binodenoson	Adenosine receptor A2a	Ki (nM)	81	N/A	N/A	Details