title: Exploring the structure-activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1.
abstract: 3-iodothyronamine (1, T1AM) is a naturally occurring derivative of thyroid hormone that can potently activate the orphan G protein-coupled receptor (GPCR) known as the trace amine-associated receptor 1 (TAAR1). We have previously found that modifying the outer ring of the phenoxyphenethylamine core scaffold of 1 can improve potency and provide potent agonists. In this study, we explored the tolerance of rat and mouse TAAR1 (rTAAR1 and mTAAR1) for structural modifications in the ethylamine portion of 1. We found that incorporating unsaturated hydrocarbon substituents and polar, hydrogen-bond-accepting groups were beneficial for rTAAR1 and mTAAR1, respectively, providing compounds that were equipotent or more potent than 1. Additionally, we have discovered that a naphthyl group is an excellent isosteric replacement for the iodophenyl ring of 1.
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California at San Francisco, California 94143-2280, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Tan
authors.forename: Motonori
authors.initials: M
authors.lastname: Miyakawa
authors.forename: James R
authors.initials: JR
authors.lastname: Bunzow
authors.forename: David K
authors.initials: DK
authors.lastname: Grandy
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship; D013970:Thyronines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000095383:Trace Amine-Associated Receptors
chemical_list: D000242:Cyclic AMP; D005021:Ethylamines; D009281:Naphthalenes; D043562:Receptors, G-Protein-Coupled; D013970:Thyronines; D000095383:Trace Amine-Associated Receptors; C487948:3-iodothyronamine