title: Novel positive allosteric modulators of GABAA receptors: do subtle differences in activity at alpha1 plus alpha5 versus alpha2 plus alpha3 subunits account for dissimilarities in behavioral effects in rats?
abstract: Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia. miroslav@pharmacy.bg.ac.rs
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
authors.forename: Samarpan
authors.initials: S
authors.lastname: Majumder
authors.forename: Shengming
authors.initials: S
authors.lastname: Huang
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Edwankar
authors.forename: Roman
authors.initials: R
authors.lastname: Furtmüller
authors.forename: Srdan
authors.initials: S
authors.lastname: Joksimović
authors.forename: Terry
authors.initials: T
authors.lastname: Clayton
authors.forename: Joachim
authors.initials: J
authors.lastname: Ramerstorfer
authors.forename: Marija M
authors.initials: MM
authors.lastname: Milinković
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D008024:Ligands; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D014161:Transduction, Genetic / Q000379:methods; D014981:Xenopus
chemical_list: D018682:GABA Agents; D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines