title: Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists.
abstract: A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [3H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Amal M Y
authors.initials: AM
authors.lastname: Mohsen
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Yasmine M
authors.initials: YM
authors.lastname: Mandour
authors.forename: Edita
authors.initials: E
authors.lastname: Sarukhanyan
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Breitinger
authors.affiliation: Institute of Clinical Neurobiology, University of Würzburg , 97078 Würzburg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Villmann
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Maha M
authors.initials: MM
authors.lastname: Banoub
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Hans-Georg
authors.identifier: http://orcid.org/0000-0003-0111-3528
authors.initials: HG
authors.lastname: Breitinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Christoph
authors.identifier: http://orcid.org/0000-0003-4713-4068
authors.initials: C
authors.lastname: Sotriffer
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Faculty of Pharmacy and Biotechnology, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Darius P
authors.identifier: http://orcid.org/0000-0002-1193-3119
authors.initials: DP
authors.lastname: Zlotos
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000032:analysis / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004987:Ethers; D008024:Ligands; D010091:Oximes; D018009:Receptors, Glycine; D013331:Strychnine; D005998:Glycine