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Article

Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies

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Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
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Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia
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Molecular Biology and Nanotechnology Laboratory ([email protected]), Department of Engineering and Architecture, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy
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Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
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St. Petersburg University Hospital, St. Petersburg State University, 199034 St. Petersburg, Russia
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(11), 391; https://doi.org/10.3390/ph13110391
Received: 17 October 2020 / Revised: 11 November 2020 / Accepted: 12 November 2020 / Published: 14 November 2020
(This article belongs to the Section Medicinal Chemistry)
Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (116) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC50 values in functional activity at hTAAR1 and low general cytotoxicity (CC50 > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the ortho-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds 15 (2,3-diCl, EC50 = 20 nM), 2 (2-CH3, EC50 = 30 nM), 6 (2-OCH3, EC50 = 93 nM) and 3 (2-Cl, EC50 = 160 nM). Apart from the interest in them as valuable leads for the development of promising hTAAR1 agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient hTAAR1 targeting ability. View Full-Text
Keywords: trace amine-associated receptor 1 (TAAR1); human TAAR1 agonists; 1-amidino-4-phenylpiperazines; pharmacophore model; docking studies trace amine-associated receptor 1 (TAAR1); human TAAR1 agonists; 1-amidino-4-phenylpiperazines; pharmacophore model; docking studies
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MDPI and ACS Style

Francesconi, V.; Cichero, E.; Kanov, E.V.; Laurini, E.; Pricl, S.; Gainetdinov, R.R.; Tonelli, M. Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies. Pharmaceuticals 2020, 13, 391. https://doi.org/10.3390/ph13110391

AMA Style

Francesconi V, Cichero E, Kanov EV, Laurini E, Pricl S, Gainetdinov RR, Tonelli M. Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies. Pharmaceuticals. 2020; 13(11):391. https://doi.org/10.3390/ph13110391

Chicago/Turabian Style

Francesconi, Valeria, Elena Cichero, Evgeny V. Kanov, Erik Laurini, Sabrina Pricl, Raul R. Gainetdinov, and Michele Tonelli. 2020. "Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies" Pharmaceuticals 13, no. 11: 391. https://doi.org/10.3390/ph13110391

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