title: Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABA(B) receptor.
abstract: The potential efficacy of GABA(B) receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA(B) receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA(B) receptor may constitute a novel approach in the pharmacological manipulation of the GABA(B) receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA(B) PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA- and baclofen-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding to native GABA(B) receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA(B) receptor antagonist, 3-N-[1-((S)-3,4dichlorophenyl)-ethylaminol]-2-(S)hydroxypropyl cyclo-hexylmethyl phosphinic acid ([(3)H]CGP54626)], both COR627 and COR628 increased the affinity of high- and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA(B) receptor.
authors: Department of Neuroscience Bernard B. Brodie, University of Cagliari, Cagliari, Italy. castelli@unica.it
authors: M Paola
authors: MP
authors: Castelli
authors: Angelo
authors: A
authors: Casu
authors: Paola
authors: P
authors: Casti
authors: Carla
authors: C
authors: Lobina
authors: Mauro A M
authors: MA
authors: Carai
authors: Giancarlo
authors: G
authors: Colombo
authors: Maurizio
authors: M
authors: Solinas
authors: Daniela
authors: D
authors: Giunta
authors: Claudia
authors: C
authors: Mugnaini
authors: Serena
authors: S
authors: Pasquini
authors: Andrea
authors: A
authors: Tafi
authors: Simone
authors: S
authors: Brogi
authors: Gian Luigi
authors: GL
authors: Gessa
authors: Federico
authors: F
authors: Corelli
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001665:Binding Sites; D018757:GABA Modulators / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D018757:GABA Modulators; D018080:Receptors, GABA-B; D013876:Thiophenes; C571282:methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate; C571283:methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001418:Baclofen; D010424:Pentobarbital; D000218:Adamantane