Click Modification in the N^sup 6^ Region of A^sub 3^ Adenosine Receptor-Selective Carbocyclic Nucleosides for Dendrimeric Tethering that Preserves Pharmacophore Recognition

Adenosine derivatives were modified with alkynyl groups on ... substituents for linkage to carriers using Cu(I)-catalyzed click chemistry. Two parallel series, both containing a rigid North-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, behaved as ... adenosine receptor (AR) agonists: (5'-methyluronamides) or partial agonists (4'-truncated). Terminal alkynyl groups on a chain at the 3 position of a ...-benzyl group or simply through a ...-propargyl group were coupled to azido derivatives, which included both small molecules and G4 (fourth-generation) multivalent poly(amidoamine) (PAMAM) dendrimers, to form 1,2,3-triazolyl linkers. The small molecular triazoles probed the tolerance in ... binding of distal, sterically bulky groups such as 1-adamantyl. Terminal 4-fluoro-3-nitrophenyl groups anticipated nucleophilic substitution for chain extension and ... radiolabeling. ...-(4-Fluoro-3-nitrophenyl)-triazolylmethyl derivative 32 displayed a ... of 9.1 nM at ... with 1000-fold subtype selectivity. Multivalent conjugates additionally containing click-linked water-solubilizing polyethylene glycol groups potently activated ... in the 5'-methyluronamide, but not 4' truncated series. N6-Benzyl nucleoside conjugate 43 (apparent ... 24 nM) maintained binding affinity of the monomer better than a ...-triazolylmethyl derivative. Thus, the ... region of 5'-methyluronamide derivatives, as modeled in receptor docking, is suitable for functionalization and tethering by click chemistry to achieve high ... agonist affinity and enhanced selectivity. (ProQuest: ... denotes formulae/symbols omitted.)