Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer's Disease Agents.
The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neurodegenerative disorders such as Alzheimer's disease, effectively preventing or slowing the progression of the disease. Hence, in the search for a more effective treatment for Alzheimer's disease, in this paper, the multitarget-directed ligand paradigm was applied to the design of carbamates able to simultaneously target the recently proposed endocannabinoid system and the classic cholinesterase system, and achieve effective dual FAAH/cholinesterase inhibitors. Among the two series of synthesized compounds, while some derivatives proved to be extremely potent on a single target, compounds 9 and 19 were identified as effective dual FAAH/ChE inhibitors, with well-balanced nanomolar activities. Thus, 9 and 19 might be considered as new promising candidates for Alzheimer's disease treatment.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Serena
S
Montanari
Department of Pharmacy, University of Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Laura
L
Scalvini
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Manuela
M
Bartolini
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Federica
F
Belluti
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Silvia
S
Gobbi
Department for Life Quality Studies, Alma Mater Studiorum University of Bologna , Corso d'Augusto 237, 47921 Rimini, Italy.
Vincenza
V
Andrisano
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council , Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy.
Alessia
A
Ligresti
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council , Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy.
Vincenzo
V
Di Marzo
Department of Pharmacy, University of Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Silvia
S
Rivara
Department of Pharmacy, University of Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Marco
M
Mor
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Alessandra
A
Bisi
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
Angela
A
Rampa
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000110:Acetylcholinesterase; D000581:Amidohydrolases; D002091:Butyrylcholinesterase; D002219:Carbamates; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases