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J Med Chem. 2016 Apr 14;59(7):3249-63. doi: 10.1021/acs.jmedchem.5b01998. Epub 2016 Feb 18.

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.

Author information

1
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
2
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
3
Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.

Abstract

Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) 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 A3AR 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 A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR 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 A3AR binding site.

PMID:
26890707
PMCID:
PMC4970510
DOI:
10.1021/acs.jmedchem.5b01998
[Indexed for MEDLINE]
Free PMC Article

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