Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Alessandra Pecorelli, Sandra Gemma, Mauro Maccarrone, Stefania Butini, Giuseppe Campiani, Ettore Novellino, Fabrizio Micheli, Giuseppe Valacchi, Massimo Valoti, Manuela Fantacci, Mascia Benedusi, Alessandro Grillo, Stefania Lamponi, Andrea Wong, Elisabetta Perdona, Laura Castelletti, Domenico Fazio, Filomena Fezza, Nicola Relitti, Margherita Brindisi, Simone Brogi, Giulia Chemi

Journal: European journal of medicinal chemistry 2020;183():111674

PMID: 31518969

Full Text on Elsevier Science View on PubMed

Abstract

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D or D receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.

Address: Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.; Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.; Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131, Napoli, Italy.; Department of Experimental Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133, Rome, Italy.; Faculty of Biosciences and Technology for Food Agriculture and Environment, University of Teramo, via R. Balzarini 1, 64100, Teramo, Italy; Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy.; Aptuit (Verona) Srl, an Evotec Company, Via Alessandro Fleming, 4, 37135, Verona, Italy.; NC State University, Plants for Human Health Institute, 600 Laureate Way, Kannapolis, NC, 28081, USA.; Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy.; Department of Life Sciences, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.; NC State University, Plants for Human Health Institute, 600 Laureate Way, Kannapolis, NC, 28081, USA; Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy. Electronic address: [email protected].; Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy. Electronic address: [email protected].; Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy; European Center for Brain Research, Santa Lucia Foundation IRCCS, Via del Fosso di Fiorano snc, 00176, Rome, Italy.

DOI: 10.1016/j.ejmech.2019.111674

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MeSH Terms: Amidohydrolases, Binding, Competitive, Cell Line, Cell Survival, Dopamine, Endocannabinoids, Enzyme Inhibitors, Humans, Ligands, Piperazines, Pyrroles