4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones. A New Series of CNS Stimulants<sup>1</sup>

Lunsford, Carl D.; Cale, Albert D.; Ward, John W.; Franko, Bernard V.; Jenkins, H. O.

doi:10.1021/jm00333a012

Cited by 35 publications

(10 citation statements)

References 1 publication

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“…Unlike TFP and AXPN, which are both psychoactive drugs, DXP is a breathing stimulant that causes an increase in tidal volume and respiratory rate through stimulation of chemoreceptors in the carotid bodies independent of oxygen levels (68,69). Similar to the case for TFP and AXPN, the therapeutic dose of DXP Three hours prior to infection, mice were treated with a single dose of TFP (1.5 mg/kg) or vehicle alone by the i.p.…”

Section: Discussionmentioning

confidence: 99%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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h Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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“…A number of selective, high-potency TASK-blocking compounds have been identified, and some are in clinical use or have undergone preclinical studies (Putzke et al, 2007;Brendel et al, 2009;Streit et al, 2011;Coburn et al, 2012;Flaherty et al, 2014). Doxapram is a breathing stimulant and carotid body-activating drug developed in the 1960s for use in human and veterinary medicine (Lunsford et al, 1964). Doxapram may act on TASK-1/TASK-3 heterodimeric channels, which provide the predominant hypoxia-sensitive background potassium conductance in rodent carotid body glomus cells (Cotten et al, 2006;Kim et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

et al. 2015

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Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ9-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K 2P ) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118-128 and 228-248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC 50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded.

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“…For example, an analgesic and sedative action has been established for 1,5-diphenyl-3-butylpyrrolidine-2,4-dione (Habicht, 1962). Derivatives of the pyrrolidin-2-ones have also been shown to have an important effect on the central nervous system (Lunsford, Cale, Ward, Franko & Jenkins, 1964). As part of a systematic study of pyrrole and succinimide derivatives we have carried out an X-ray analysis of (I) (Engel, 1972).…”

Section: Institut Fffr Organische Chemie Der Technischenmentioning

confidence: 99%

1,3-Dioxole-2-spiro-4'-(3',3'-diethylpyrrolidin-2'-one)

Sheldrick¹,

Borkenstein²,

Engel³

1978

Acta Crystallogr Sect B

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4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones. A New Series of CNS Stimulants¹

Cited by 35 publications

References 1 publication

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

1,3-Dioxole-2-spiro-4'-(3',3'-diethylpyrrolidin-2'-one)

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4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones. A New Series of CNS Stimulants1

Cited by 35 publications

References 1 publication

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

1,3-Dioxole-2-spiro-4'-(3',3'-diethylpyrrolidin-2'-one)

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4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones. A New Series of CNS Stimulants¹