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Dopamine-derived N 6 -substituents, compared to N 6 -(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A 3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, K i = 10.9/17.8 nM, at human/mouse A 3 AR). 15 was a partial agonist in vitro (hA 3 AR, cAMP inhibition, 31% E max AR in vitro. Distal H-bonding substitutions of the 3 AR, [ 35 S]GTP-γ-S binding, 16% E max ) and in vivo and also antagonized hA 3 AR in vitro. Distal H-bonding substitutions of the N 6 -(2-phenylethyl) moiety particularly enhanced mA 3 AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA 3 AR and hA 3 AR homology models. These hybrid models were based on an inactive antagonist-bound hA 1 AR structure for the upper part of TM2 and an agonist-bound hA 2A AR structure for the remaining TM portions. These species-independent A 3 AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A 3 AR, a drug target of growing interest.

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.

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.

The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues. Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetranorprostaglandin F2alpha is a very active inducer of luteolysis in laboratory animals and cattle.

Various chemically stable prostaglandin analogues were studied for their affinity towards the PGD2-receptor in human platelet membranes in order to define the requirements for specific ligand binding to this receptor. On replacing the 11- or 9-hydroxyl groups of PGF2 alpha by an 11 alpha- or 9 beta-chloro- or fluoro atom, stable prostaglandin analogues were obtained, which showed high affinity towards the PGD2-receptor. The lower side chain consisted of a 15-cyclohexyl group or of the natural 15-n-pentyl group, other substitutents decreased the affinity substantially. The highest PGD2-mimetic activity with a relative affinity of 0.5 to the PGD2-receptor was found in 9-deoxy-9 beta-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-PGF2 alpha (ZK 110 841, compound 16 in Table 1). ZK 110 841 is a chemically stable crystalline substance, which is orally active and which might thus turn out to be an interesting tool for the study of PGD2-receptor interactions. Some other prostaglandin as well as prostacyclin analogues with a 15-cyclohexyl or 15-n-pentyl group exhibited in addition to their known high affinity to the PGE2-receptor of human uterine membranes or the PGI2-receptor of human platelets also affinities to the PGD2-receptor. Generally, the receptor affinities correlate with the activities as stimulators of adenylate cyclase and inhibitors of thrombin induced elevation of cytoplasmic free calcium as well as their ability to inhibit ADP-induced platelet aggregation. The PGI2-character regarding the effector systems prevails in compounds with affinity to both the PGI2- and PGD2-receptor. Compounds which bind to the PGE2- and PGD2-receptor show a flat dose response curve regarding platelet activation suggesting a mixture of pro- and antiaggregatory properties within these molecules.