Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A(3) adenosine receptor (A(3)AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A(3)AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A(3)AR K-i values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A(3)AR (MRS7220, K-i 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 mu mol/kg, po). The lack of a C6 H-bond donor while maintaining A(3)AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A(3)AR binding site.
Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists
Ciancetta ASecondo
;
2016
Abstract
Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A(3) adenosine receptor (A(3)AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A(3)AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A(3)AR K-i values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A(3)AR (MRS7220, K-i 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 mu mol/kg, po). The lack of a C6 H-bond donor while maintaining A(3)AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A(3)AR binding site.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.