ABSTRACT
Dopamine-derived N6-substituents, compared to N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions of the N6-(2-phenylethyl) moiety particularly enhanced mA3AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA3AR and hA3AR homology models. These hybrid models were based on an inactive antagonist-bound hA1AR structure for the upper part of TM2 and an agonist-bound hA2AAR structure for the remaining TM portions. These species-independent A3AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A3AR, a drug target of growing interest.
Subject(s)
Adenosine A3 Receptor Agonists/chemistry , Adenosine A3 Receptor Agonists/metabolism , Nucleosides/chemistry , Nucleosides/metabolism , Receptor, Adenosine A3/chemistry , Receptor, Adenosine A3/metabolism , Adenosine A3 Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nucleosides/pharmacology , Protein Binding/drug effects , Protein Binding/physiology , Protein Structure, SecondaryABSTRACT
The synthesis of new ansa(1)-N(4)5-ethylene cytidines such as 3-ss-D-ribofuranosyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,3-d]pyrimidin-2-one is described and the problems connected with the ring closure to the desired tetrahydro-2H-pyrrolo[2,3-d]pyrimidine base discussed. The lack of biological activities of the new ansa(1-) cytidines is furthermore commented on.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cytidine/analogs & derivatives , Cytidine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , Cytidine/chemical synthesis , Humans , Mice , Models, MolecularABSTRACT
This unit describes, in detail, the optimized condition for the synthesis of nucleosides making use of the trimethysilyl triflate-mediated silyl-Hilbert-Johnson synthesis. This unit focuses on the mechanistic understanding of this universal and conveniently applicable method.