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 language | English |
|---|---|
| Article number | 111674 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 183 |
| DOIs | |
| Publication status | Published - Dec 1 2019 |
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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
Cite this
Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems. / Grillo, Alessandro; Chemi, Giulia; Brogi, Simone; Brindisi, Margherita; Relitti, Nicola; Fezza, Filomena; Fazio, Domenico; Castelletti, Laura; Perdona, Elisabetta; Wong, Andrea; Lamponi, Stefania; Pecorelli, Alessandra; Benedusi, Mascia; Fantacci, Manuela; Valoti, Massimo; Valacchi, Giuseppe; Micheli, Fabrizio; Novellino, Ettore; Campiani, Giuseppe; Butini, Stefania; Maccarrone, Mauro; Gemma, Sandra.
In: European Journal of Medicinal Chemistry, Vol. 183, 111674, 01.12.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems
AU - Grillo, Alessandro
AU - Chemi, Giulia
AU - Brogi, Simone
AU - Brindisi, Margherita
AU - Relitti, Nicola
AU - Fezza, Filomena
AU - Fazio, Domenico
AU - Castelletti, Laura
AU - Perdona, Elisabetta
AU - Wong, Andrea
AU - Lamponi, Stefania
AU - Pecorelli, Alessandra
AU - Benedusi, Mascia
AU - Fantacci, Manuela
AU - Valoti, Massimo
AU - Valacchi, Giuseppe
AU - Micheli, Fabrizio
AU - Novellino, Ettore
AU - Campiani, Giuseppe
AU - Butini, Stefania
AU - Maccarrone, Mauro
AU - Gemma, Sandra
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Dopamine ligands
KW - Dopamine receptor ligands
KW - Endocannabinoid system
KW - Enzyme inhibitors
KW - Fatty acid amide hydrolase
KW - Multitarget compounds
KW - Polypharmacology
KW - Selective inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85071982708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071982708&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2019.111674
DO - 10.1016/j.ejmech.2019.111674
M3 - Article
AN - SCOPUS:85071982708
VL - 183
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 111674
ER -