Novel biguanide-based derivatives scouted as TAAR1 agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies.
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.
Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy. Electronic address: michele.tonelli@unige.it.
Michele
M
Tonelli
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Stefano
S
Espinoza
Institute of Translational Biomedicine, St. Petersburg State University, 199034, St. Petersburg, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow Region, Russia.
Raul R
RR
Gainetdinov
Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy. Electronic address: cichero@unige.it.
Elena
E
Cichero
D065966:Absorption, Physicochemical; D000818:Animals; D001645:Biguanides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000095383:Trace Amine-Associated Receptors
D001645:Biguanides; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C582062:TAAR5 protein, mouse
Benzyl biguanide derivatives; Murine and human TAAR1 agonists; Phenyl biguanide derivatives; Trace amine-associated receptors (TAARs)