6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
Fabrizio
F
Micheli
Paolo
P
Cavanni
Daniele
D
Andreotti
Roberto
R
Arban
Roberto
R
Benedetti
Barbara
B
Bertani
Michela
M
Bettati
Letizia
L
Bettelini
Giorgio
G
Bonanomi
Simone
S
Braggio
Renzo
R
Carletti
Anna
A
Checchia
Mauro
M
Corsi
Elettra
E
Fazzolari
Stefano
S
Fontana
Carla
C
Marchioro
Emilio
E
Merlo-Pich
Michele
M
Negri
Beatrice
B
Oliosi
Emiliangelo
E
Ratti
Kevin D
KD
Read
Maja
M
Roscic
Ilaria
I
Sartori
Simone
S
Spada
Giovanna
G
Tedesco
Luca
L
Tarsi
Silvia
S
Terreni
Filippo
F
Visentini
Alessandro
A
Zocchi
Laura
L
Zonzini
Romano
R
Di Fabio
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D017551:Microdialysis; D008958:Models, Molecular; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D053961:Azabicyclo Compounds; D006536:Heptanes; D014179:Neurotransmitter Uptake Inhibitors; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine