Trace amines (TAs), such as -phenylethylamine (-PEA), tyramine, 3-iodothyronamine (T1AM), octopamine, tryptamine and synephrine, are found at low levels in multiple tissues in the periphery and brain of mammals but their physiological functions remain enigmatic. A recent discovery of a family of rhodopsin-like G protein-coupled receptors (GPCRs), defined as Trace Amine-Associated Receptors (TAARs), has provided an opportunity to explore the roles of TAs and their receptors in physiology and disease. The human TAAR family consists of six genes and three pseudogenes and characterized by location on a single chromosome, high overall sequence homology to monoamine receptors, and the presence of a TAAR-specific peptide fingerprint motif with the seventh transmembrane domain that is not found in all other known GPCRs. It is believed that the TAAR family most likely evolved from a common ancestor gene sharing closest similarity to the human gene encoding serotonin 5-HT4 receptor via a series of gene duplication events . Human and murine TAAR1 (h/mTAAR1) are expressed in a variety of tissues including brain, stomach, kidney, lung and intestine, but not in the olfactory epithelium (OE). On the contrary, with the exception of hTAAR1, all human TAARs proved to be exclusively expressed in small areas of olfactory sensory neurons (OSNs) in the OE . Recently, several research groups focused their efforts to investigate TAAR5 receptor pharmacology and, up to now, only one compound has been proved to act as TAAR5 agonist: trimethylamine (TMA) . Up to now, being TAs able to interact with all the TAARs receptor, selective hTAAR5 ligands are still unknown. On the other hand, trimethylamine proved to be the only TAAR5 agonist described in literature. In this context, with the aim of identifying specific and selective ligands for TAAR5, we built an homology model of the receptor, which first of all allowed us to explore which different amino acids can be involved in the binding of hTAAR5 ligands. Furthermore, we used the derived model as a tool for virtual screening analyses. In particular, we focused our attention on an in-house database of compounds, which already proved to be active as 5HT1A ligands. The selected database includes a series of aryloxyalchylamines and N1-arylpiperazines obtained by combining 30 different scaffolds bearing a flexible or a rigid basic core. The scaffolds were chosen within a series of substituted 1,3-dioxolane, 1,3-oxathiolane, 1,3-dithiolane, spiro-dioxolane, 1,4-dioxane, tetrahydrofuran, cyclopentanone-, cyclopentanol based compounds, previously discussed and published by some of us [4 and literature cited therein]. Following this procedure, we identified one compound (1) which proved to be a selective TAAR5 antagonist.
Insights into the structure of the Human TAAR5 receptor: a computational study / Cichero, E.; Espinoza, S.; Franchini, Silvia; D'Ursi, P.; Gainetdinov, R. R.; Brasili, Livio; Milanesi, L.; Fossa, P.. - (2014), pp. 99-100.
|Data di pubblicazione:||2014|
|Titolo:||Insights into the structure of the Human TAAR5 receptor: a computational study|
|Autore/i:||Cichero, E.; Espinoza, S.; Franchini, Silvia; D'Ursi, P.; Gainetdinov, R. R.; Brasili, Livio; Milanesi, L.; Fossa, P.|
|Data del convegno:||4-6 March 2014|
|Luogo del convegno:||Auditorium of Aptuit Center for Drug Discovery & Development, Verona, Italy|
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