In Vitro and In Vivo Sequestration of Methamphetamine by a Sulfated Acyclic CB[n]-Type Receptor

Abstract

We report the synthesis of two new acyclic sulfated acyclic CB[n]-type receptors (TriM0 and Me₄ TetM0) and investigations of their binding properties toward a panel of drugs of abuse (1-13) by a combination of ¹ H NMR spectroscopy and isothermal titration calorimetry. TetM0 is the most potent receptor with K_a ≥10⁶ M^-1 toward methamphetamine, fentanyl, MDMA and mephedrone. TetM0 is not cytotoxic toward HepG2 and HEK 293 cells below 100 μM according to MTS metabolic and adenylate kinase release assays and is well tolerated in vivo when dosed at 46 mg kg^-1 . TetM0 does not inhibit the hERG ion channel and is not mutagenic based on the Ames fluctuation test. Finally, in vivo efficacy studies show that the hyperlocomotion of mice treated with methamphetamine can be greatly reduced by treatment with TetM0 up to 5 minutes later. TetM0 has potential as a broad spectrum in vivo sequestrant for drugs of abuse.

Keywords: cucurbituril; hyperlocomotion; methamphetamine; molecular recognition; sequestration agents.