1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Micheli
Fabrizio
F
Psychiatry Centre of Excellence, Molecular Discovery Research, and Safety Assessment, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
Bonanomi
Giorgio
G
Blaney
Frank E
FE
Braggio
Simone
S
Capelli
Anna Maria
AM
Checchia
Anna
A
Curcuruto
Ornella
O
Damiani
Federica
F
Fabio
Romano Di
RD
Donati
Daniele
D
Gentile
Gabriella
G
Gribble
Andy
A
Hamprecht
Dieter
D
Tedesco
Giovanna
G
Terreni
Silvia
S
Tarsi
Luca
L
Lightfoot
Andrew
A
Stemp
Geoff
G
Macdonald
Gregor
G
Smith
Alex
A
Pecoraro
Michela
M
Petrone
Marcella
M
Perini
Ornella
O
Piner
Jacqui
J
Rossi
Tino
T
Worby
Angela
A
Pilla
Maria
M
Valerio
Enzo
E
Griffante
Cristiana
C
Mugnaini
Manolo
M
Wood
Martyn
M
Scott
Claire
C
Andreoli
Michela
M
Lacroix
Laurent
L
Schwarz
Adam
A
Gozzi
Alessandro
A
Bifone
Angelo
A
Ashby
Charles R
CR
Hagan
Jim J
JJ
Heidbreder
Christian
C
D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D000428:Alcohol Drinking / Q000517:prevention & control; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors*; D011969:Receptors, Histamine H1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014029:Tobacco Use Disorder / Q000517:prevention & control; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C524269:7-(1,3-dimethyl-1H-pyrazol-5-yl)-3-(3-((4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl)thio)propyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; D001552:Benzazepines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D014230:Triazoles; D003042:Cocaine; D000109:Acetylcholine