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.

IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities

“…In a recent development, the γ-cyclodextrin sugammadex was chemically modified to encapsulate rocuronium and reverse neuromuscular blockade by forming a stable host-guest inclusion complex and removing the drug from the neuromuscular junction [87,88]. Whether encapsulation of rocuronium in this manner can mitigate an existing anaphylactic reaction induced by rocuronium remains to be proven but it has already been suggested that allergenicity may be retained due to incomplete encapsulation of the molecule in the inclusion complex form.…”

Slow Actions of Neuroactive Steroids at GABAAReceptors

“…We probed these ideas using cyclodextrins, cyclic sugar molecules with a hydrophobic core region within which cholesterol (Szejtli, 1998) and at least some steroids (Adam et al, 2002) fit. Cyclodextrins have been used to manipulate plasma membrane cholesterol content (Yancey et al, 1996;Haynes et al, 2000;Westover et al, 2003).…”

“…We hypothesized that the slow kinetics of these currents arises from accumulation of steroid into a reservoir, likely the plasma membrane, from which the ligand accesses a site on the GABA receptor. Support for this idea came from studies using ␥-cyclodextrin as a soluble, hydrophobic "sponge" (Adam et al, 2002). The presence of ␥-cyclodextrin significantly speeded the offset kinetics of directly gated neurosteroid currents.…”

Synthesis of cyclodextrin derivatives with monosaccharides and their binding with ampicillin and selected lectins

“…HATU-mediated amide bond formation between 2ꞌ-aminoethyl-appended monosaccharides and the per-carboxyethylthio-terminated cyclodextrin derivatives 1 and 2 16 and the novel monocarboxy-derivative 7 (Scheme 1) gave the monodisperse products 3-6 and 8-9, respectively, whereas using HOBT/DCC coupling under numerous conditions (ratio, temperature, duration) products of inferior quality were obtained. The monosaccharides with 2ꞌ-aminoethyl linkers were synthesized according to literature methods from the parent monosaccharides: 2ꞌ-aminoethyl-α-D-mannopyranose was prepared in five steps and 59% overall yield 17 and 2ꞌ-aminoethyl-2-acetamide-2-deoxy-α-D-glucopyranose was prepared in three steps and 69% overall yield from the known azido precursor.…”