Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase.
We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1.To understand the unexpected affinity for the CB1receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.
Alessio
A
De Simone
Debora
D
Russo
Gian Filippo
GF
Ruda
Alessandra
A
Micoli
Mariarosaria
M
Ferraro
Rita Maria Concetta
RM
Di Martino
Giuliana
G
Ottonello
Maria
M
Summa
Andrea
A
Armirotti
Tiziano
0000-0002-2496-2701
T
Bandiera
FaBit, Università di Bologna , 40127 Bologna, Italy.
Andrea
A
Cavalli
BiKi Technologies , 16163 Genova, Italy.
Giovanni
0000-0003-1251-583X
G
Bottegoni
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003412:Cricetulus; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D000077489:Piperazine; D010879:Piperazines; D050637:Receptors, Dopamine D3; D000099252:Fatty Acid Amide Hydrolases; C010574:biphenyl