title: In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs.
abstract: An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M(-1)) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2·NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2·NMBA complex with the formation of the 2·drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2·NMBA complex, the Ka of the AChR·NMBA complex, the Ka of the 2·drug complex, and the dosage of the drug.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Ganapati
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Zavalij
authors.forename: Matthias
authors.initials: M
authors.lastname: Eikermann
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D009466:Neuromuscular Blocking Agents / Q000737:chemistry / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099246:Cucurbit(n)urils
chemical_list: D047028:Macrocyclic Compounds; D009466:Neuromuscular Blocking Agents; D011950:Receptors, Cholinergic; D000099246:Cucurbit(n)urils