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

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 Ka ≥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.

Anthracene-Walled Acyclic CB[n] Receptors: in†vitro and in†vivo Binding Properties toward Drugs of Abuse.

We report studies of the interaction of six acyclic CB[n]-type receptors toward a panel of drugs of abuse by a combination of isothermal titration calorimetry and 1 H NMR spectroscopy. Anthracene walled acyclic CB[n] host (M3) displays highest binding affinity toward methamphetamine (Kd =15 nM) and fentanyl (Kd =4 nM). Host M3 is well tolerated by Hep G2 and HEK 293 cells up to 100 µM according to MTS metabolic and adenylate kinase release assays. An in vivo maximum tolerated dose study with Swiss Webster mice showed no adverse effects at the highest dose studied (44.7 mg kg-1 ). Host M3 is not mutagenic based on the Ames fluctuation test and does not inhibit the hERG ion channel. In vivo efficacy studies showed that pretreatment of mice with M3 significantly reduces the hyperlocomotion after treatment with methamphetamine, but M3 does not function similarly when administered 30 seconds after methamphetamine.