Affiliation:
1. Department of Psychology University of Nebraska at Kearney Kearney NE, 69949 USA
2. Department of Biology University of Nebraska at Kearney Kearney NE, 69949 USA
3. Department of Chemistry University of Nebraska at Kearney Kearney NE, 69949 USA
4. Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA
Abstract
AbstractCircadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N‐acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X‐ray crystal‐based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine‐indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5‐carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency.
Funder
National Institutes of Health
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology