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 a7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human a7 n-AChRs (K i of 2274 and 1471 nM, respectively). Ex vivo 3 [H]a-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 ¼ 8 mg/kg p.o.). In functional studies performed with human a7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity ¼ 51 and 36%, EC 50 ¼ 4.4 and 0.9 mM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small a-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic a7 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 mM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the a7 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.) dosedependently 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 a7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2, 9-dihydro-1H-pyrido [3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABA A receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABA A receptors containing á 1 (K i = 6.8 nM) and á 2 (K i = 12.3 nM) subunits, and weaker affinity for á 5 -containing GABA A receptors (K i = 117 nM). Studies on recombinant rat GABA A receptors confirm these findings and indicate intermediate affinity for the á 3 â 2 ã 2 subtype. SL651498 behaves as a full agonist at recombinant rat GABA A receptors containing á 2 and á 3 subunits, and as a partial agonist at recombinant GABA A receptors expressing á 1 and á 5 subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg /kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential 3
␥-aminobutyric acid type A (GABA A ) receptors comprise a subfamily of ligand-gated ion channels whose activity can be modulated by ligands acting at the benzodiazepine binding site on the receptor. The benzodiazepine binding site was characterized using a site-directed mutagenesis strategy in which amino acids of the ␣ 5 subunit were substituted by their corresponding ␣ 1 residues. Given the high affinity and selectivity of ␣ 1 -containing compared with ␣ 5 -containing GABA A receptors for zolpidem, mutated ␣ 5 subunits were co-expressed with  2 and ␥ 2 subunits, and the affinity of recombinant receptors for zolpidem was measured. One ␣ 5 mutant (bearing P162T, E200G, and T204S) exhibited properties similar to that of the ␣ 1 subunit, notably high affinity zolpidem binding and potentiation by zolpidem of GABA-induced chloride current. Two of these mutations, ␣ 5 P162T and ␣ 5 E200G, might alter binding pocket conformation, whereas ␣ 5 T204S probably permits formation of a hydrogen bond with a proton acceptor in zolpidem. These three amino acid substitutions also influenced receptor affinity for CL218872. Our data thus suggest that corresponding amino acids of the ␣ 1 subunit, particularly ␣ 1 -Ser 204, are the crucial residues influencing ligand selectivity at the binding pocket of ␣ 1 -containing receptors, and a model of this binding pocket is presented.
These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.
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