title: Determination of the microscopic equilibrium dissociation constants for risedronate and its analogues reveals two distinct roles for the nitrogen atom in nitrogen-containing bisphosphonate drugs.
abstract: Microscopic equilibrium dissociation constants, k as, were determined for four nitrogen-containing bisphosphonates (N-BP): risedronate and its analogues 2-(2-aminophenyl)-1-hydroxyethylidene-1,1-bisphosphonate, NE 11807, and NE 97220. The proportion of each and of analogues 2-(3'-( N-ethyl)pyridinium)-ethylidenebisphosphonate and 2-(3-piperinidyl)-1-hydroxyethylidene-1,1-bisphosphonate, having a positively charged nitrogen and three negative charges on the bisphosphonate group ("carbocation analogue") at pH 7.5, was calculated. When set in order of increasing potency at inhibiting farnesyl diphosphate (FDP) synthase (their intracellular target), the N-BPs are also ranked in order of decreasing mole fraction of carbocation analogue. However, only a weak correlation exists between potency for inhibiting FDP synthase and potency for inhibiting Dictyostelium discoideum growth. It is concluded that, although high potency for inhibiting FDP synthase is favored when the nitrogen atom in a N-BP is uncharged, N-BPs having a positively charged nitrogen can still be potent inhibitors of Dictyostelium growth owing to favorable interaction with a second, unidentified target.
authors.affiliation: Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, UK.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Hounslow
authors.forename: John
authors.initials: J
authors.lastname: Carran
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Brown
authors.forename: Dominik
authors.initials: D
authors.lastname: Rejman
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Watts
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents; D004023:Dictyostelium / Q000187:drug effects / Q000254:growth & development; D004164:Diphosphonates / Q000737:chemistry*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008853:Microscopy / Q000379:methods*; D009584:Nitrogen / Q000737:chemistry*; D020543:Proteome; D000068296:Risedronic Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D020543:Proteome; D000068296:Risedronic Acid; D012968:Etidronic Acid; D009584:Nitrogen