title: 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.
abstract: 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.
authors.affiliation: 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
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bonanomi
authors.forename: Frank E
authors.initials: FE
authors.lastname: Blaney
authors.forename: Simone
authors.initials: S
authors.lastname: Braggio
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Capelli
authors.forename: Anna
authors.initials: A
authors.lastname: Checchia
authors.forename: Ornella
authors.initials: O
authors.lastname: Curcuruto
authors.forename: Federica
authors.initials: F
authors.lastname: Damiani
authors.forename: Romano Di
authors.initials: RD
authors.lastname: Fabio
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Andy
authors.initials: A
authors.lastname: Gribble
authors.forename: Dieter
authors.initials: D
authors.lastname: Hamprecht
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tedesco
authors.forename: Silvia
authors.initials: S
authors.lastname: Terreni
authors.forename: Luca
authors.initials: L
authors.lastname: Tarsi
authors.forename: Andrew
authors.initials: A
authors.lastname: Lightfoot
authors.forename: Geoff
authors.initials: G
authors.lastname: Stemp
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.forename: Alex
authors.initials: A
authors.lastname: Smith
authors.forename: Michela
authors.initials: M
authors.lastname: Pecoraro
authors.forename: Marcella
authors.initials: M
authors.lastname: Petrone
authors.forename: Ornella
authors.initials: O
authors.lastname: Perini
authors.forename: Jacqui
authors.initials: J
authors.lastname: Piner
authors.forename: Tino
authors.initials: T
authors.lastname: Rossi
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: Maria
authors.initials: M
authors.lastname: Pilla
authors.forename: Enzo
authors.initials: E
authors.lastname: Valerio
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Manolo
authors.initials: M
authors.lastname: Mugnaini
authors.forename: Martyn
authors.initials: M
authors.lastname: Wood
authors.forename: Claire
authors.initials: C
authors.lastname: Scott
authors.forename: Michela
authors.initials: M
authors.lastname: Andreoli
authors.forename: Laurent
authors.initials: L
authors.lastname: Lacroix
authors.forename: Adam
authors.initials: A
authors.lastname: Schwarz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
mesh_terms: 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
chemical_list: 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