19 Dec Molecular Containers May Be Able to Bind and Reverse Effects of Dangerous Addictive Drugs
MedicalResearch.com Interview with:
Prof. Isaacs
Lyle Isaacs, Professor
University of Maryland Department of Chemistry and BiochemistryCollege Park, MD 20742
MedicalResearch.com: What is the background for this study?
Response: The Isaacs laboratory has a long-standing interest in molecular containers compounds and their molecular recognition properties toward chemically and biologically important targets. Molecular containers include well known pharmaceutical excipients that help dissolve and deliver drugs (e.g. sulfobutyl-beta-cyclodextrin (SBE-b-CD)) and even sequester active pharmaceutical ingredients (e.g. Sugammadex reverses the effects of neuromuscular blockers).
Our lab has previously studied a class of molecular containers called cucurbiturils and found that they bind tightly (nanomolar Kd) to hydrophobic cations in aqueous solution. Recently, we translated our knowledge of tight binding to design and synthesize a novel tight binding molecular container known as Pillar[6]MaxQ and showed that it has superior binding affinity toward hydrophobic cations.[reference = Angewandte Chemie International Edition 2020, 59, 13313]
MedicalResearch.com: What are the main findings?
Response: In this Chem paper, we take the next steps and showed that Pillar[6]MaxQ binds strongly to a panel of drugs of abuse, especially Methamphetamine, Fentantyl, PCP, mephedrone, and MDMA. Pillar[6]MaxQ was shown to have good biocompatibility according to a battery of in vitro cytotoxicity tests and in vivo maximum tolerated dose studies. Pillar[6]MaxQ does not inhibit the hERG ion channel and is not mutagenic according to the Ames fluctuation test. Open field tests were used to demonstrate the effect of Pillar[6]MaxQ on the hyperlocomotion of animals that had been previously dosed with methamphetamine (0.5 mg/kg) or fentanyl (0.1 mg/kg). We find that Pillar[6]MaxQ (35.7 mg/kg for methamphetamine and 5 mg/kg for fentanyl) effectively reverses the hyperlocomotive effects of methamphetamine and fentanyl when administered 5 minutes after methamphetamine or 15 minutes after fentanyl.
MedicalResearch.com: What should readers take away from your report?
Two things:
1) The Pillar[6]MaxQ is an efficient in vivo sequestrant for methamphetamine and fentanyl with potential broader spectrum activity toward MDMA, PCP, and mephedrone.
2) That Sugammadex is not the only molecular container that can be used as an in vivo reversal agent for selected drugs.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: Future preclinical work on this topic should be directed toward:
1) The further optimization of the dose and timing of Pillar[6]MaxQ to reverse the effects of methamphetamine and fentanyl and other members of the drugs of abuse panel,
2) Additional toxicology studies of Pillar[6]MaxQ in different animals, and 3) the development of an efficient process scale synthetic route to Pillar[6]MaxQ.
Disclosures: Dr. Isaacs is an advisor, consultant, and holds stock options in Clear Scientific (Cambridge, MA).
Citation:
Adam T. Brockett, Weijian Xue, David King, Chun-Lin Deng, Canjia Zhai, Michael Shuster, Shivangi Rastogi, Volker Briken, Matthew R. Roesch, Lyle Isaacs,
Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl, Chem, 2022, ISSN 2451-9294,
https://doi.org/10.1016/j.chempr.2022.11.019.
(https://www.sciencedirect.com/science/article/pii/S2451929422006180)
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Last Updated on December 19, 2022 by Marie Benz MD FAAD