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

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Cyclodextrin-based nanonutrients (CB[n]) are explored for drug sequestration.
• Development of novel acyclic CB[n]-type receptors is ongoing.
• Need for effective sequestrants for drugs of abuse.

Purpose of the Study:

• Synthesize and characterize new sulfated acyclic CB[n]-type receptors.
• Investigate binding affinities of novel receptors toward drugs of abuse.
• Evaluate the safety and in vivo efficacy of the most potent receptor.

Main Methods:

• Synthesis of acyclic sulfated CB[n]-type receptors (TriM0 and Me4 TetM0).
• Binding studies using 1H NMR spectroscopy and isothermal titration calorimetry.
• Cytotoxicity assays (MTS, adenylate kinase release), hERG channel inhibition, Ames test, and in vivo efficacy studies in mice.

Main Results:

• TetM0 demonstrated high binding affinity (Ka ≥10^6 M^-1) for methamphetamine, fentanyl, MDMA, and mephedrone.
• TetM0 exhibited no cytotoxicity in HepG2 and HEK 293 cells below 100 μM.
• TetM0 was well-tolerated in vivo and did not inhibit the hERG ion channel or show mutagenicity.
• In vivo studies showed TetM0 significantly reduced methamphetamine-induced hyperlocomotion in mice.

Conclusions:

• TetM0 is a potent and safe receptor for multiple drugs of abuse.
• TetM0 shows potential as a broad-spectrum in vivo sequestrant for drug abuse treatment.
• Further development of TetM0 could lead to novel therapeutic strategies for substance abuse.