title: SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile.
abstract: In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
authors.affiliation: Central Nervous System Research Department, Sanofi-Aventis, Bagneux, France. bruno.biton@sanofi-aventis.com
authors.forename: Bruno
authors.initials: B
authors.lastname: Biton
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Bergis
authors.forename: Frédéric
authors.initials: F
authors.lastname: Galli
authors.forename: Alain
authors.initials: A
authors.lastname: Nedelec
authors.forename: Alistair W
authors.initials: AW
authors.lastname: Lochead
authors.forename: Samir
authors.initials: S
authors.lastname: Jegham
authors.forename: Danielle
authors.initials: D
authors.lastname: Godet
authors.forename: Christophe
authors.initials: C
authors.lastname: Lanneau
authors.forename: Raphaël
authors.initials: R
authors.lastname: Santamaria
authors.forename: Françoise
authors.initials: F
authors.lastname: Chesney
authors.forename: Jacques
authors.initials: J
authors.lastname: Léonardon
authors.forename: Patrick
authors.initials: P
authors.lastname: Granger
authors.forename: Marc W
authors.initials: MW
authors.lastname: Debono
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bohme
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sgard
authors.forename: François
authors.initials: F
authors.lastname: Besnard
authors.forename: David
authors.initials: D
authors.lastname: Graham
authors.forename: Annick
authors.initials: A
authors.lastname: Coste
authors.forename: André
authors.initials: A
authors.lastname: Oblin
authors.forename: Olivier
authors.initials: O
authors.lastname: Curet
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
authors.forename: Corinne
authors.initials: C
authors.lastname: Voltz
authors.forename: Liliane
authors.initials: L
authors.lastname: Rouquier
authors.forename: Josiane
authors.initials: J
authors.lastname: Souilhac
authors.forename: Vincent
authors.initials: V
authors.lastname: Santucci
authors.forename: Christiane
authors.initials: C
authors.lastname: Gueudet
authors.forename: Dominique
authors.initials: D
authors.lastname: Françon
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Florence
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.forename: Patrick
authors.initials: P
authors.lastname: Avenet
authors.forename: Bernard
authors.initials: B
authors.lastname: Scatton
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid