title: Stable 9 beta- or 11 alpha-halogen-15-cyclohexyl-prostaglandins with high affinity to the PGD2-receptor.
abstract: 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.
authors.affiliation: Institute of Pharmacology, Research Laboratories of Schering AG, Berlin, West, Federal Republic of Germany.
authors.forename: K H
authors.initials: KH
authors.lastname: Thierauch
authors.forename: C S
authors.initials: CS
authors.lastname: Stürzebecher
authors.forename: E
authors.initials: E
authors.lastname: Schillinger
authors.forename: H
authors.initials: H
authors.lastname: Rehwinkel
authors.forename: B
authors.initials: B
authors.lastname: Radüchel
authors.forename: W
authors.initials: W
authors.lastname: Skuballa
authors.forename: H
authors.initials: H
authors.lastname: Vorbrüggen
mesh_terms: D000262:Adenylyl Cyclases / Q000097:blood; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000097:blood; D006219:Halogens / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000378:metabolism*
chemical_list: D006219:Halogens; D011453:Prostaglandins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015230:Prostaglandin D2; D002118:Calcium; C036293:prostaglandin D2 receptor