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.

Grillo, A., Chemi, G., Brogi, S., Brindisi, M., Relitti, N., Fezza, F., et al. (2019). Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 183, 1-23 [10.1016/j.ejmech.2019.111674].

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems

Grillo A.;Chemi G.;Brindisi M.;Relitti N.;Lamponi S.;Pecorelli A.;Valoti M.;Campiani G.;Butini S.
;
Gemma S.
2019-01-01

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.
Grillo, A., Chemi, G., Brogi, S., Brindisi, M., Relitti, N., Fezza, F., et al. (2019). Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 183, 1-23 [10.1016/j.ejmech.2019.111674].
File in questo prodotto:
File Dimensione Formato  
Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.pdf

non disponibili

Tipologia: PDF editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 4.86 MB
Formato Adobe PDF
4.86 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Manuscript_revised.pdf

accesso aperto

Descrizione: Bozza post peer-review accettata per la pubblicazione
Tipologia: Post-print
Licenza: Creative commons
Dimensione 2.63 MB
Formato Adobe PDF
2.63 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1080077