title: Toward deciphering the code to aminergic G protein-coupled receptor drug design.
abstract: The trace amine-associated receptor 1 (TAAR(1)) is a biogenic amine G protein-coupled receptor (GPCR) that is potently activated by 3-iodothyronamine (1, T(1)AM) in vitro. Compound 1 is an endogenous derivative of the thyroid hormone thyroxine which rapidly induces hypothermia, anergia, and bradycardia when administered to mice. To explore the role of TAAR(1) in mediating the effects of 1, we rationally designed and synthesized rat TAAR(1) superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation. The functional activity of a ligand is proposed to be correlated to its probable interactions with the rotamer switch residues; agonists allow the rotamer switch residues to toggle to their active conformation, whereas antagonists interfere with this conformational transition. These agonist and antagonist design principles provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties.
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Tan
authors.forename: Eli S
authors.initials: ES
authors.lastname: Groban
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000818:Animals; D015195:Drug Design; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013970:Thyronines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000095383:Trace Amine-Associated Receptors
chemical_list: D043562:Receptors, G-Protein-Coupled; D013970:Thyronines; D000095383:Trace Amine-Associated Receptors; C487948:3-iodothyronamine