Date Approved
9-5-2024
Embargo Period
9-6-2025
Document Type
Thesis
Degree Name
Master of Science (M.S.)
Department
Pharmaceutical Sciences
College
College of Science & Mathematics
Advisor
Thomas Keck, Ph.D.
Committee Member 1
Subash Jonnalagadda, Ph.D.
Committee Member 2
Kandalam Ramanujachary, Ph.D.
Keywords
pharmokinetics, neuropsychiatric disorders, dopamine receptors, brain chemistry, neurophysiology
Subject(s)
Drugs--Design; Mental illness--Treatment
Disciplines
Chemicals and Drugs | Medicinal-Pharmaceutical Chemistry
Abstract
Several neurophysiological functions, such as attention, cognition, and emotional regulation, are regulated by the binding of dopamine on G-Protein coupled receptors. D4Rs are mainly located in the prefrontal cortex and the hippocampus and are known to have a key role in decision-making, memory formation, cognition, and attention. Administration of D4Rs- selective ligands during the preclinical studies enhance the outcomes and the results in animal models suffering from neuropsychiatric disorders, including ADHD, substance use disorders (SUD), and Alzheimer's disease. Recently, we reported a group of D4R-selective ligands with different efficacies depending on their phenylpiperazine ring scaffold to illustrate D4R function during the preclinical studies. However, in-vivo studies reported the rapid metabolism of some compounds due to the cleavage of amide linkage during phase I metabolism, limiting further investigation. Therefore, using click chemistry methods, we bioisosterically replace the amide bond with a 1,2,3-triazole linkage and reveal a novel of D4R-selective ligands. In-vitro studies indicate that the pharmacodynamics profile for 1,2,3-triazole compounds has similar functional and binding characteristics to the amide linkage analogs with more tolerability profiles towards phase I metabolism. Behavioral studies in rats using 1,2,3-triazoles are still ongoing.
Recommended Citation
Alkhatib, Mohammad, "IMPROVING LIGAND PHARMACOKINETICS VIA BIOISOSTERIC SUBSTITUTION OF AMIDES WITH 1, 2, 3-TRIAZOLES WHILE MAINTAINING DOPAMINE D4 RECEPTOR SELECTIVITY AND POTENCY" (2024). Theses and Dissertations. 3283.
https://rdw.rowan.edu/etd/3283
