title: Synthesis and pharmacological characterization of 2-(acylamino)thiophene derivatives as metabolically stable, orally effective, positive allosteric modulators of the GABAB receptor.
abstract: Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABAB receptor by potentiating GTPγS stimulation induced by GABA at 2.5 and 25 μM while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro, Siena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Valentina
authors.initials: V
authors.lastname: Pedani
authors.forename: Angelo
authors.initials: A
authors.lastname: Casu
authors.forename: Carla
authors.initials: C
authors.lastname: Lobina
authors.forename: Alberto
authors.initials: A
authors.lastname: Casti
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Porcu
authors.forename: Daniela
authors.initials: D
authors.lastname: Giunta
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Solinas
authors.forename: Stefania
authors.initials: S
authors.lastname: Dragoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Castelli
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004355:Drug Stability; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D041681:NIH 3T3 Cells; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D018080:Receptors, GABA-B / Q000737:chemistry* / Q000378:metabolism*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018080:Receptors, GABA-B; D013876:Thiophenes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001418:Baclofen; D010424:Pentobarbital