Pillar[6]MaxQ: A Potent Supramolecular Host for In Vivo Sequestration of Methamphetamine and Fentanyl

Pillar[6]MaxQ (P6AS) functions as an in vivo sequestration agent for methamphetamine and fentanyl. We use ¹H NMR, isothermal titration calorimetry, and molecular modelling to deduce the geometry and strength of the P6AS•drug complexes. P6AS forms tight complexes with fentanyl (K_d=9.8 nM), PCP (17.1 nM), MDMA (25.5 nM), mephedrone (52.4 nM), and methamphetamine (101 nM). P6AS has good in vitro biocompatibility according to MTS metabolic, Adenylate Kinase cell death, and hERG ion channel inhibition assays, and the Ames fluctuation test. The no observed adverse effect level for P6AS is 45 mg/kg. The hyperlocomotion of mice treated with methamphetamine (0.5 mg/kg) can be ameliorated by treatment with P6AS (35.7 mg/kg) 5-minutes later, whereas the hyperlocomotion of mice treated with fentanyl (0.1 mg/kg) can be controlled by treatment with P6AS (5 mg/kg) up to 15-minutes later. P6AS has significant potential for development as a broad spectrum in vivo sequestration agent.