Novel biguanide-based derivatives scouted as TAAR1 agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies

Michele Tonelli; Stefano Espinoza; Raul R Gainetdinov; Elena Cichero

doi:10.1016/j.ejmech.2016.10.058

Novel biguanide-based derivatives scouted as TAAR1 agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies

Eur J Med Chem. 2017 Feb 15:127:781-792. doi: 10.1016/j.ejmech.2016.10.058. Epub 2016 Oct 27.

Authors

Michele Tonelli¹, Stefano Espinoza², Raul R Gainetdinov³, Elena Cichero⁴

Affiliations

¹ Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy. Electronic address: michele.tonelli@unige.it.
² Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
³ Institute of Translational Biomedicine, St. Petersburg State University, 199034, St. Petersburg, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow Region, Russia.
⁴ Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy. Electronic address: cichero@unige.it.

PMID: 27823885
DOI: 10.1016/j.ejmech.2016.10.058

Abstract

Trace amines (TAs) are endogenous neuromodulators that play a functional role in the synaptic transmission within central nervous system (CNS), targeting trace amine-associated receptors (TAARs). Starting from our previous computational studies on TAAR1 and TAAR5 interactions with the unselective ligand 3-iodothyronamine (T₁AM), we investigated the functional activity at murine and human TAAR1 and murine TAAR5 receptors of twenty-seven biguanide-based derivatives, including six newly synthesized compounds. Phenyl (BIG2, BIG4, BIG8 and BIG22) or benzyl (BIG10-BIG16) biguanides were found to be selective murine and human TAAR1 agonists with potencies in nanomolar or low micromolar range, respectively. In particular, compounds BIG2 and BIG12-BIG14 were the most promising and they could be considered valuable lead compounds worthy of further investigations. In addition to the interest for developing more effective human TAAR1 ligands, the disclosed here potent murine TAAR1 agonists could offer suitable tools for studying the pharmacology of TAAR1 receptor.

Keywords: Benzyl biguanide derivatives; Murine and human TAAR1 agonists; Phenyl biguanide derivatives; Trace amine-associated receptors (TAARs).

MeSH terms

Absorption, Physicochemical*
Animals
Biguanides / chemical synthesis*
Biguanides / chemistry
Biguanides / metabolism
Biguanides / pharmacology*
Chemistry Techniques, Synthetic
Computer Simulation
Drug Design*
Humans
Mice
Molecular Docking Simulation*
Protein Conformation
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship

Substances

Biguanides
Receptors, G-Protein-Coupled
trace amine-associated receptor 5, mouse
Trace amine-associated receptor 1