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.
Micheli
Fabrizio
F
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
Cavanni
Paolo
P
Andreotti
Daniele
D
Arban
Roberto
R
Benedetti
Roberto
R
Bertani
Barbara
B
Bettati
Michela
M
Bettelini
Letizia
L
Bonanomi
Giorgio
G
Braggio
Simone
S
Carletti
Renzo
R
Checchia
Anna
A
Corsi
Mauro
M
Fazzolari
Elettra
E
Fontana
Stefano
S
Marchioro
Carla
C
Merlo-Pich
Emilio
E
Negri
Michele
M
Oliosi
Beatrice
B
Ratti
Emiliangelo
E
Read
Kevin D
KD
Roscic
Maja
M
Sartori
Ilaria
I
Spada
Simone
S
Tedesco
Giovanna
G
Tarsi
Luca
L
Terreni
Silvia
S
Visentini
Filippo
F
Zocchi
Alessandro
A
Zonzini
Laura
L
Di Fabio
Romano
R
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