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Abstract: This report describes the in vitro features of a novel selective nicotinic acetylcholine receptor (nAChR) α7 agonist, JN403, (S)-(1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid (S)-1-(2-fluoro-phenyl)-ethyl ester. JN403 was evaluated in a number of in vitro systems of different species, at recombinant receptors using radioligand binding, signal transduction and electrophysiological studies. When using [125I] α-bungarotoxin (α-BTX) as a radioligand, JN403 has high affinity for human recombinant nAChR α7 (pK D =6.7). Functionally, JN403 is a partial and potent agonist at human nAChR α7. The compound stimulates calcium influx in GH3 cells recombinantly expressing the human nAChR with an pEC50 of 7.0 and an E max of 85% (compared to the full agonist epibatidine). In Xenopus oocytes expressing human nAChR α7 JN403 induces inward currents with an pEC50 of 5.7 and an E max of 55%. In both recombinant systems JN403 is a partial agonist and the agonistic effects are blocked after pre-administration of methyllycaconitine (MLA, 100nM), a nAChR α7 antagonist. In functional calcium influx assays, JN403 displays a significantly lower potency for other subtypes of human nAChRs like α4β2, α3β4, α1β1γδ as well as 5HT3 receptors when tested functionally as an antagonist (pIC50 <4.8) and is devoid of agonistic activity (pEC50 <4). Similarly, JN403 shows low binding activity at a wide panel of neurotransmitter receptors. Thus, JN403 is a potent and selective nAChR α7 agonist and will be a useful tool for the characterization of nAChR α7 mediated effects both in vitro and in vivo. [Copyright &y& Elsevier]

Abstract: A novel series of agonists at the benzodiazepine binding site of the GABAA receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either α2- or α1-containing GABAA receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure–activity relationship and efforts to increase in vitro stabilities are discussed. [Copyright &y& Elsevier]

Abstract: A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED50 of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage. [Copyright &y& Elsevier]

Abstract: A novel class of α7 nicotinic acetylcholine receptor (nAChR) agonists has been discovered through high-throughput screening. The cis γ-lactam scaffold has been optimized to reveal highly potent and selective α7 nAChR agonists with in vitro activity and selectivity and with good brain penetration in mice. [Copyright &y& Elsevier]

Abstract: Several lines of evidence suggest that the nicotinic acetylcholine receptor α7 (nAChR α7) is involved in central nervous system disorders like schizophrenia and Alzheimer''s disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR α7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR α7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety. [Copyright &y& Elsevier]

Abstract: The neuronal nicotinic acetylcholine receptor α7 (nAChR α7) may be involved in cognitive deficits in Schizophrenia and Alzheimer''s disease. A fast pharmacological characterization of homomeric α7 receptors is mostly hampered by their low functional expression levels in heterologous expression systems. In the present study expression of homomeric nAChR α7 was achieved in GH3 rat pituitary cells. α7 Subunits were heterologously expressed as components of [125I]-labeled α-bungarotoxin binding nAChRs (B max: 1.2pmol/mg protein). Function of the expressed α7 ion channels was assessed by patch-clamp recording and calcium imaging. While acetylcholine-induced currents desensitized within much less than 1s, calcium-sensitive fluorescence transients peaked after 5–10s and returned to background levels within 30s only. The fluorescence signal was blocked by isradipine and removal of extracellular sodium indicated that in these cells opening of rapidly desensitizing α7 nAChR triggers calcium influx via voltage-gated, DHP-sensitive calcium channels. In this cellular system, agonists revealed the following rank order of potency: epibatidine>anatoxin A>AAR17779>ABT-594>DMPP>nicotine>GTS-21>cytisine>ABT-418>acetylcholine>choline>ABT-089. All of the signals were inhibited by the α7 antagonists α-bungarotoxin (pIC50: 7.4) and methyllycaconitine (pIC50: 7.8). Further, marketed antidepressants showed antagonistic activity with the following rank order of potency: fluoxetine>imipramine>paroxetine>sertraline. These data illustrate that coupling to voltage-gated calcium channels allows a rapid and reliable functional examination of nAChR α7. [Copyright &y& Elsevier]