1,2,4-Triazolyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists.
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Micheli
Fabrizio
F
Neurosciences Centre of Excellence, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
Arista
Luca
L
Bonanomi
Giorgio
G
Blaney
Frank E
FE
Braggio
Simone
S
Capelli
Anna Maria
AM
Checchia
Anna
A
Damiani
Federica
F
Di-Fabio
Romano
R
Fontana
Stefano
S
Gentile
Gabriella
G
Griffante
Cristiana
C
Hamprecht
Dieter
D
Marchioro
Carla
C
Mugnaini
Manolo
M
Piner
Jacqui
J
Ratti
Emiliangelo
E
Tedesco
Giovanna
G
Tarsi
Luca
L
Terreni
Silvia
S
Worby
Angela
A
Ashby
Charles R
CR
Heidbreder
Christian
C
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D006168:Guinea Pigs; D006586:Hexanes / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D023421:Models, Animal; D008956:Models, Chemical; D015394:Molecular Structure; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006586:Hexanes; D050637:Receptors, Dopamine D3