Discipline: Chemistry and Chemical Sciences
Subcategory: Chemistry (not Biochemistry)
Mason A. Baber - Rollins College
Co-Author(s): Deanna Montgomery, University of Michigan, Ann Arbor, MI; Jessica P. Anand, University of Michigan, Ann Arbor, MI; Lennon Delong, University of Michigan, Ann Arbor, MI; John R. Traynor, University of Michigan, Ann Arbor, MI; Henry I. Mosberg, University of Michigan, Ann Arbor, MI
Studies have shown that activation of the kappa opioid receptor (KOR) can reduce cocaine self-administration, presumably by inhibiting dopamine production and/or release. However, KOR agonism also causes dysphoria, or intense unease and discontent. The introduction of partial agonism at the mu opioid receptor (MOR) may provide an opportunity to overcome this side effect due to its ability to induce euphoria. Multifunctional ligands with a KOR/MOR profile could potentially be used to curb or treat cocaine addiction. Recently, modifications and additions to the DMT-Tic scaffold have been made, and the resulting compounds demonstrate this desired profile. This work expands on that research by synthesizing novel compounds with various substituted benzyl and acetophenone pendants at the 7 position of the tetrahydroisoquinoline core and evaluating them for binding affinity, efficacy, and potency at KOR and MOR. The benzyl pendant compounds with electron-withdrawing groups at the ortho position demonstrated a KOR agonist/MOR partial agonist profile while the meta-hydroxy benzyl pendant compound showed a more balanced profile. The acetophenone pendant compounds exhibited a preference in efficacy at MOR over KOR.
Funder Acknowledgement(s): NIH Grant DA003910; NIH Grant DA033397; NSF-funded Interdisciplinary REU Program in the Structure and Function of Proteins at the University of Michigan College of Pharmacy; University of Michigan Community College Summer Fellow Program
Faculty Advisor: Henry I. Mosberg, firstname.lastname@example.org
Role: My role in this research was synthesizing and characterizing organic compounds using standard techniques and characterization methods (i.e. NMR, HRMS) to be assessed for biological activity.