Enhancing Ligand Pharmacokinetics While Retaining Dopamine D4 Receptor Potency and Selectivity via Bioisosteric Substitution of Amide Linkers with 1,2,3-Triazoles

Abstract ID 101080 Poster Board 288 The neurotransmitter dopamine signals through G protein-coupled receptors to modulate various neurophysiological functions. Activation of dopamine D4 receptors (D4Rs), predominantly located in the brain's prefrontal cortex and hippocampal regions, can modulate memory formation, attention, decision-making, and cognition. Prior studies indicate that D4R-selective ligands are efficacious in preclinical models of cognitive disorders and substance use disorders. Recently, we reported a library of novel D4R-selective ligands with varying efficacies for further preclinical study. Unfortunately, these compounds exhibited rapid in vivo metabolism precluding proper evaluation of their behavioral effects. In vitro pharmacokinetics (PK) studies revealed that the primary route of drug metabolism was the cleavage of an amide linker present in the scaffold of these compounds. In this study, we bioisosterically replaced the amide bond with a 1,2,3-triazole linkage using click chemistry methods and evaluated triazole analogs against their amide counterparts in binding, functional, and PK studies. Our results indicate that 1,2,3-triazole analogs sustained high D4R binding and selectivity over dopamine D2 and D3 receptors. Overall, triazole analogs have markedly similar functional profiles at D2-like receptors, indicating no loss of in vitro function. Finally, liver microsome studies, replacement of the amide linkage with a 1,2,3-triazole substantially increases drug half-lives in rats with minor improvements in humans, and eliminates non-Phase I metabolism (i.e., via amidases). These new analogs represent a set of new molecular tools better equipped to further explore D4R signaling in rodent models of neuropsychiatric disorders. DA050896, DA058385, GM136492