Insights into the Structure and Pharmacology of the Human Trace Amine‐Associated Receptor 1 (hTAAR1): Homology Modelling and Docking Studies. (28th March 2013)

• Record Type: Journal Article
• Authors: Cichero, Elena; Espinoza, Stefano; Gainetdinov, Raul R.; Brasili, Livio; Fossa, Paola
• Is Part Of: Chemical biology & drug design. Volume 81:Number 4(2013:Apr.)
• Page Start: 509
• Page End: 516
• Publication Date: 2013-03-28
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12018
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Trace amine‐associated receptor 1 (TAAR1) is a G protein–coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β‐phenylethylamine (<bold>β‐PEA</bold>) and 3‐iodothyronamine (<bold>T</bold><sub><bold>1</bold></sub><bold>AM</bold>). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist <bold>RO5166017</bold> has been identified. To explore the molecular mechanisms of protein–agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the <italic>h</italic>TAAR1. The putative protein‐binding site has been explored by comparing the <italic>h</italic>TAAR1 model with the β<sub>2</sub>‐adrenoreceptor binding site, available by X‐ray crystallization studies, and with the homology modelled 5HT<sub>1A</sub> receptor. The obtained results, in tandem with docking studies performed with <bold>RO5166017</bold>, <bold>β‐PEA</bold> and <bold>T</bold><sub><bold>1</bold></sub><bold>AM</bold>, provided an opportunity to reasonably identify the <italic>h</italic>TAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.</p> </abstract>