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Bioorganic and Medicinal Chemistry Letters
Volumn 24, Issue 1, 2014, Pages 288-293
Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allosteric modulator of alpha-7 nicotinic acetylcholine receptors: Attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral administration
Author keywords

Electrophysiology; Lead optimization; Nicotinic acetylcholine receptors; Novel object recognition; Positive allosteric modulator
Indexed keywords

AF 58801; BUNGAROTOXIN; BUNGAROTOXIN RECEPTOR; NICOTINIC RECEPTOR BLOCKING AGENT; PHENCYCLIDINE; UNCLASSIFIED DRUG; CENTRAL NERVOUS SYSTEM AGENTS; NICOTINIC AGENT;
EID: 84891488508     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2013.11.022     Document Type: Article
Times cited : (29)
References (29)
  • 12
    • 84891488750 scopus 로고    scopus 로고
    • As the nAChα7 receptor is a calcium permeable ion channel, the activity of this receptor can be measured in cell lines expressing the target using calcium sensitive dyes. In this paper, we used a rat GH4C1 cell line with stable expression of nAChα7 receptors. The cells were seeded in 384-well plates and loaded with a calcium sensitive dye (calcium-4). The α7 receptor was activated with 20 μM ACh and the activity of new compounds was measured as a change in fluorescence between control ± compounds, measured on a FDSS 700 reader. PNU-120596 was used as positive control and the max stimulation of new compounds was calculated relative to PNU-120596 defined as 100%.
    • As the nAChα7 receptor is a calcium permeable ion channel, the activity of this receptor can be measured in cell lines expressing the target using calcium sensitive dyes. In this paper, we used a rat GH4C1 cell line with stable expression of nAChα7 receptors. The cells were seeded in 384-well plates and loaded with a calcium sensitive dye (calcium-4). The α7 receptor was activated with 20 μM ACh and the activity of new compounds was measured as a change in fluorescence between control ± compounds, measured on a FDSS 700 reader. PNU-120596 was used as positive control and the max stimulation of new compounds was calculated relative to PNU-120596 defined as 100%.
  • 13
    • 84891488611 scopus 로고    scopus 로고
    • All aqueous solubilities were determined in phosphate buffer pH 7.4 based on crystalline material. For 2 the aqueous solubility measurement was based on crystalline or partly crystalline material.
    • All aqueous solubilities were determined in phosphate buffer pH 7.4 based on crystalline material. For 2 the aqueous solubility measurement was based on crystalline or partly crystalline material.
  • 14
    • 84891493313 scopus 로고    scopus 로고
    • c log P was calculated using Daylight Version 4.9 from Daylight Chemical Information Systems, Inc.
    • c log P was calculated using Daylight Version 4.9 from Daylight Chemical Information Systems, Inc.
  • 15
    • 84891485465 scopus 로고    scopus 로고
    • The absolute configuration was performed by comparing optical rotary power with literature values.
    • The absolute configuration was performed by comparing optical rotary power with literature values.
  • 16
    • 84891484824 scopus 로고    scopus 로고
    • 50 values and maximum stimulation was calculated for the new compounds. Retigabine was used as standard positive control.
    • 50 values and maximum stimulation was calculated for the new compounds. Retigabine was used as standard positive control.
  • 17
    • 84891489610 scopus 로고    scopus 로고
    • 3) Kozikowski et al., J. Med. Chem. 2009, 52, 1885; Lit: [α] D 20 = + 311.7 (c 1.776, EtOH) Walborsky et al., Tetrahedron 1964, 20, 1695).
    • 3) Kozikowski et al., J. Med. Chem. 2009, 52, 1885; Lit: [α] D 20 = + 311.7 (c 1.776, EtOH) Walborsky et al., Tetrahedron 1964, 20, 1695).
  • 19
    • 84891487389 scopus 로고    scopus 로고
    • In all cases, the dextrorotary trans 2-phenyl-cyclopropanecarboxylic acids were used for further synthesis.
    • In all cases, the dextrorotary trans 2-phenyl-cyclopropanecarboxylic acids were used for further synthesis.
  • 29
    • 84891483078 scopus 로고    scopus 로고
    • Male Lister Hooded rats (Charles River, Crl:LH, Germany; 220-240 g) were administered subPCP (synthesized at H. Lundbeck A/S, dissolved in 0.9% saline; 5 mg/kg, 1 ml/kg, ip bid for 7 days) or saline (1 ml/kg ip bid for 7 days) at 7 am and 7 pm, followed by a 7-day washout period prior to behavioural testing. Lu AF58801 (dissolved in 100% PEG400) was administered 30 min prior to the acquisition trial of the NOR procedure via the po route. Data is presented as the discrimination index, calculated as the novel object exploration time (Tn) minus the familiar object exploration time (Tf) divided by the total exploration time (Tn + Tf). One-way ANOVA, followed by appropriate All-Pairwise Multiple Comparison post-hoc analysis (Bonferroni's t-test) was used to investigate statistical differences between test groups (P < 0.05).
    • Male Lister Hooded rats (Charles River, Crl:LH, Germany; 220-240 g) were administered subPCP (synthesized at H. Lundbeck A/S, dissolved in 0.9% saline; 5 mg/kg, 1 ml/kg, ip bid for 7 days) or saline (1 ml/kg ip bid for 7 days) at 7 am and 7 pm, followed by a 7-day washout period prior to behavioural testing. Lu AF58801 (dissolved in 100% PEG400) was administered 30 min prior to the acquisition trial of the NOR procedure via the po route. Data is presented as the discrimination index, calculated as the novel object exploration time (Tn) minus the familiar object exploration time (Tf) divided by the total exploration time (Tn + Tf). One-way ANOVA, followed by appropriate All-Pairwise Multiple Comparison post-hoc analysis (Bonferroni's t-test) was used to investigate statistical differences between test groups (P < 0.05).

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