title: Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.
abstract: A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
authors.affiliation: Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse ML1 5SH, Scotland, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Adam
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: Anton
authors.initials: A
authors.lastname: Bom
authors.forename: John K
authors.initials: JK
authors.lastname: Clark
authors.forename: Helen
authors.initials: H
authors.lastname: Feilden
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hutchinson
authors.forename: Ronald
authors.initials: R
authors.lastname: Palin
authors.forename: Alan
authors.initials: A
authors.lastname: Prosser
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Rosair
authors.forename: Donald
authors.initials: D
authors.lastname: Stevenson
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Tarver
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zhang
mesh_terms: D000732:Androstanols / Q000737:chemistry*; D000818:Animals; D018360:Crystallography, X-Ray; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D003473:Neuromuscular Nondepolarizing Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000077123:Rocuronium; D055672:Static Electricity; D013329:Structure-Activity Relationship; D000077122:Sugammadex; D047408:gamma-Cyclodextrins
chemical_list: D000732:Androstanols; D003505:Cyclodextrins; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077123:Rocuronium