In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs. Issue 4 (9th December 2015)

• Record Type: Journal Article
• Authors: Ganapati, Shweta; Zavalij, Peter Y.; Eikermann, Matthias; Isaacs, Lyle
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 4(2016)
• Page Start: 1277
• Page End: 1287
• Publication Date: 2015-12-09
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c5ob02356d
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : We measure the binding affinity of Calabadion 2 toward 27 drugs to assess its selectivity toward rocuronium, vecuronium, and cisatracurium. 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 of2 to bind NMBAs rocuronium and cisatracurium in vitro . We measured the binding affinities ( K a, M −1 ) of twenty seven commonly used drugs towards2 and simulated the equilibrium between2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of2 ·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 with2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the2 ·NMBA complex with the formation of the2 ·drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the K a of the2 ·NMBA complex, the K a of the AChR·NMBA complex, the K a of the2 ·drug complex, and the dosage of the drug.