Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents
AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In pre...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Future Pharmacology |
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| Online Access: | https://www.mdpi.com/2673-9879/4/1/12 |
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| author | Daniel Pierce Radin Sheng Zhong Rok Cerne Mohammed Shoaib Jeffrey M. Witkin Arnold Lippa |
| author_facet | Daniel Pierce Radin Sheng Zhong Rok Cerne Mohammed Shoaib Jeffrey M. Witkin Arnold Lippa |
| author_sort | Daniel Pierce Radin |
| collection | DOAJ |
| description | AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms. |
| first_indexed | 2024-04-24T18:16:25Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2673-9879 |
| language | English |
| last_indexed | 2024-04-24T18:16:25Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Future Pharmacology |
| spelling | doaj.art-f0c6232b2cb84a4db749d1ea71f2646a2024-03-27T13:42:21ZengMDPI AGFuture Pharmacology2673-98792024-02-014117318710.3390/futurepharmacol4010012Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in RodentsDaniel Pierce Radin0Sheng Zhong1Rok Cerne2Mohammed Shoaib3Jeffrey M. Witkin4Arnold Lippa5RespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452, USAPsychogenics, 215 College Road, Paramus, NJ 07652, USARespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452, USASchool of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UKRespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452, USARespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452, USAAMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms.https://www.mdpi.com/2673-9879/4/1/12ADHDampakineAMPA receptorhyperactivityLTPopiate-induced respiratory depression |
| spellingShingle | Daniel Pierce Radin Sheng Zhong Rok Cerne Mohammed Shoaib Jeffrey M. Witkin Arnold Lippa Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents Future Pharmacology ADHD ampakine AMPA receptor hyperactivity LTP opiate-induced respiratory depression |
| title | Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents |
| title_full | Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents |
| title_fullStr | Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents |
| title_full_unstemmed | Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents |
| title_short | Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents |
| title_sort | low impact ampakine cx1739 exerts pro cognitive effects and reverses opiate induced respiratory depression in rodents |
| topic | ADHD ampakine AMPA receptor hyperactivity LTP opiate-induced respiratory depression |
| url | https://www.mdpi.com/2673-9879/4/1/12 |
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