Presentation Title

Discovery of New Potent FAAH Inhibitors: Synthesis, Biological Evaluation and In Silico Molecular Docking Studies

Faculty Mentor

Stevan Pecic

Start Date

23-11-2019 10:00 AM

End Date

23-11-2019 10:45 AM

Location

109

Session

poster 3

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

There are three known classes of cannabinoids: phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Endocannabinoids, such as anandamide (AEA) demonstrates to produce pain alleviation effect, such as analgesia, and anti-inflammation, with low side effects. Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme that is responsible for the metabolizing of AEA. The goal of our lab is to develop novel therapeutics for pain management by inhibiting FAAH and thus, preventing the degradation of AEA. We have designed, synthesized and evaluated a new series of amide-based FAAH inhibitors. Using threestep linear synthesis, we successfully synthesized 11 compounds. Our synthesis started with EDC-amide coupling reaction, followed by removal of the Boc protecting group using trifluoroacetic acid (TFA). The obtained amine was reacted with various different sulfonyl chlorides to yield the target analogs in moderate yields. These small molecules were found to inhibit the human FAAH enzyme in moderate to low nanomolar range. In order to better understand the binding modes and interactions of these inhibitors within the catalytic site of the human FAAH enzyme, we performed docking studies. Finally, we calculated and performed prediction of the several pharmacokinetic parameters important for the drug development process. Our structure-activity relationship (SAR) and molecular modeling studies suggest that ortho- and para-substitutions are important for the low nanomolar inhibition against the FAAH enzyme.

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Nov 23rd, 10:00 AM Nov 23rd, 10:45 AM

Discovery of New Potent FAAH Inhibitors: Synthesis, Biological Evaluation and In Silico Molecular Docking Studies

109

There are three known classes of cannabinoids: phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Endocannabinoids, such as anandamide (AEA) demonstrates to produce pain alleviation effect, such as analgesia, and anti-inflammation, with low side effects. Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme that is responsible for the metabolizing of AEA. The goal of our lab is to develop novel therapeutics for pain management by inhibiting FAAH and thus, preventing the degradation of AEA. We have designed, synthesized and evaluated a new series of amide-based FAAH inhibitors. Using threestep linear synthesis, we successfully synthesized 11 compounds. Our synthesis started with EDC-amide coupling reaction, followed by removal of the Boc protecting group using trifluoroacetic acid (TFA). The obtained amine was reacted with various different sulfonyl chlorides to yield the target analogs in moderate yields. These small molecules were found to inhibit the human FAAH enzyme in moderate to low nanomolar range. In order to better understand the binding modes and interactions of these inhibitors within the catalytic site of the human FAAH enzyme, we performed docking studies. Finally, we calculated and performed prediction of the several pharmacokinetic parameters important for the drug development process. Our structure-activity relationship (SAR) and molecular modeling studies suggest that ortho- and para-substitutions are important for the low nanomolar inhibition against the FAAH enzyme.