Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats

5 years ago

Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats

Matthias Eikermann, Maíra I. Rudolph, Shweta Ganapati, Steven Murkli, Lyle Isaacs, Peter Y. Zavalij, Flora Scheffenbichler, Stephanie D. Grabitz

We measured the affinity of five molecular container compounds (calabadions 1 and 2, CB[7], sulfocalix[4]arene, and HP-β-CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods (1H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (Ka values) spanning from <102 to >108 m−1. We also report X-ray crystal structures of CB[7]⋅methamphetamine and 1⋅methamphetamine. We found that 2, but not CB[7], was able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The bioavailability of the calabadions and their convergent building block synthesis suggest potential for further structural optimization as reversal agents for intoxication with nonopioid drugs of abuse for which no treatments are currently available. Be my guest. We measured the binding affinity of five molecular container compounds toward seven drugs of abuse and found two calabadion containers with broad spectrum affinity. X-ray crystal structures elucidated the geometry of the complexes with methamphetamine. Administration of one calabadion to rats treated with methamphetamine ameliorated the hyperlocomotive activity of the drug.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cbic.201700289