The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites
Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand b...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
European Respiratory Society
2018-03-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/4/1/00127-2017.full |
| _version_ | 1828232925003382784 |
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| author | Elena K. Schneider Rachel M. McQuade Vincenzo C. Carbone Felisa Reyes-Ortega John W. Wilson Brenda Button Ayame Saito Daniel P. Poole Daniel Hoyer Jian Li Tony Velkov |
| author_facet | Elena K. Schneider Rachel M. McQuade Vincenzo C. Carbone Felisa Reyes-Ortega John W. Wilson Brenda Button Ayame Saito Daniel P. Poole Daniel Hoyer Jian Li Tony Velkov |
| author_sort | Elena K. Schneider |
| collection | DOAJ |
| description | Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg−1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor–lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092–0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood. |
| first_indexed | 2024-04-12T19:29:59Z |
| format | Article |
| id | doaj.art-a498d9bc07ab4de0b40916533745bbe4 |
| institution | Directory Open Access Journal |
| issn | 2312-0541 |
| language | English |
| last_indexed | 2024-04-12T19:29:59Z |
| publishDate | 2018-03-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj.art-a498d9bc07ab4de0b40916533745bbe42022-12-22T03:19:22ZengEuropean Respiratory SocietyERJ Open Research2312-05412018-03-014110.1183/23120541.00127-201700127-2017The potentially beneficial central nervous system activity profile of ivacaftor and its metabolitesElena K. Schneider0Rachel M. McQuade1Vincenzo C. Carbone2Felisa Reyes-Ortega3John W. Wilson4Brenda Button5Ayame Saito6Daniel P. Poole7Daniel Hoyer8Jian Li9Tony Velkov10 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia Animal Science, AgResearch Limited, Palmerston North, New Zealand Dept of Applied Physics, Sciences Faculty, University of Granada, Granada, Spain Dept of Medicine, Monash University, The Alfred Hospital, Melbourne, Australia Dept of Medicine, Monash University, The Alfred Hospital, Melbourne, Australia Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia Dept of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia Monash Biomedicine Discovery Institute, Dept of Microbiology, Monash University, Clayton, Australia Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg−1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor–lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092–0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.http://openres.ersjournals.com/content/4/1/00127-2017.full |
| spellingShingle | Elena K. Schneider Rachel M. McQuade Vincenzo C. Carbone Felisa Reyes-Ortega John W. Wilson Brenda Button Ayame Saito Daniel P. Poole Daniel Hoyer Jian Li Tony Velkov The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites ERJ Open Research |
| title | The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| title_full | The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| title_fullStr | The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| title_full_unstemmed | The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| title_short | The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| title_sort | potentially beneficial central nervous system activity profile of ivacaftor and its metabolites |
| url | http://openres.ersjournals.com/content/4/1/00127-2017.full |
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