New insights into the structure of the trace amine‐associated receptor 2: Homology modelling studies exploring the binding mode of 3‐iodothyronamine

Abstract

Recent studies have further investigated the trace amine-associated receptor type 2 (TAAR2) pharmacology, revealing its role not only at the olfactory sensory neurons but also at the immune system, being expressed in human leucocytes. In particular, the ability of this receptor to bind the unselective TAAR ligand 3-iodo-thyronamine (T AM) was elucidated, making in the meanwhile the discovery of selective compounds a urgent need to derive much more suitable tools for studying TAARs. In this context, we developed our work on TAAR2 applying a structure-based computational protocol, including TAAR2 homology modelling and T AM docking studies. The results were compared with those we previously obtained about TAAR1, in order to point out new insights guiding for selectivity between TAAR1 and TAAR2. The in silico strategy applied allowed us to provide for the first time thorough TAAR2 homology models, which are expected to be useful tools for a further design process of more selective TAAR ligands.

Trace Amines and Their Receptors

“…This has subsequently been verified by numerous laboratories (Mühlhaus et al, 2014;Cöster et al, 2015;Chiellini et al, 2017), with 3IT also shown to act as an agonist at TAAR2 (Babusyte et al, 2013;Cichero and Tonelli, 2017) and as an inverse agonist at TAAR5 (Dinter et al, 2015c). 3IT is promiscuous, however, and also interacts with high affinity at a 2 -adrenoceptors (Regard et al, 2007;Dinter et al, 2015b), b-adrenergic receptors (Meyer and Hesch, 1983;Kleinau et al, 2011;Dinter et al, 2015a), muscarinic acetylcholine receptors (Laurino et al, 2016), transient receptor potential cation channel subfamily M member 8 ion channels (Khajavi et al, 2015;Lucius et al, 2016), various monoamine and organic anion transporters (Snead et al, 2007;Panas et al, 2010), and molecular target(s) within mitochondria, including the F 1 -F 0 ATP synthase (Cumero et al, 2012) and possibly complex III (Venditti et al, 2011).…”

“…Recent attempts have been made to apply structurebased in silico computational protocols to the development of TAAR2 homology models for the prediction of TAAR2 ligands (Cichero and Tonelli, 2017). With a consensus TAAR defining motif now identified, further development of such models is expected to provide new leads and the identification of TAAR2-selective ligands, which will be a major boost to elucidating its physiologic roles.…”

Insight of Captagon Abuse by Chemogenomics Knowledgebase-guided Systems Pharmacology Target Mapping Analyses

“…78 and docking data calculated by Cichero et al . 79 . For further validation of the binding mode, we also carried out a molecular dynamics (MD) simulation as described below.

Figure 4Detailed interactions between Amphetamine and TAAR1.

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Терморегуляторные эффекты производных трийодтиронина: in vivo исследование и обзор потенциальных нейропротекторных свойств

“…Следствием этого процесса является рассеяние избытка энергии в виде тепла. Однако применение галотана значительно угнетает норэпинефрин-индуцированный термогенез, причем этот эффект является обратимым, дозозависимым и не представляет собой вторичное следствие гипотермии и/или гипоксии [31,32]. Со своей стороны, тиронамин модулирует активность субмитохондриальных частиц и растворимой субъединицы F1 ATФазы, снижая потребление кислорода и усиливая продукцию перекиси водорода митохондриями.…”