Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems

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

Research output: Contribution to journalArticlepeer-review

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 D2 or D3 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.

Original languageEnglish
Article number111674
JournalEuropean Journal of Medicinal Chemistry
Volume183
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • Dopamine ligands
  • Dopamine receptor ligands
  • Endocannabinoid system
  • Enzyme inhibitors
  • Fatty acid amide hydrolase
  • Multitarget compounds
  • Polypharmacology
  • Selective inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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