FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice
- PMID: 36473166
- PMCID: PMC10364582
- DOI: 10.1021/acschemneuro.2c00574
FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice
Abstract
There are no approved medicines for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder. Electroencephalogram (EEG) studies show alterations in resting-state cortical EEG spectra, such as increased gamma-band power, in patients with FXS that are also observed in Fmr1 knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT1A, 5-HT1B, and 5-HT1DRs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects in Fmr1 knockout mice of an orally active 2-aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT1ARs and a potent, low-efficacy partial agonist at 5-HT7Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT1B and 5-HT1DRs. FPT's Ki values at 5-HT1B and 5-HT1DRs were <5 nM, but it had nil activity (>10 μM Ki) at 5-HT1FRs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adult Fmr1 knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and female Fmr1 knockout mice from recordings above the left somatosensory cortex (LSSC). In addition, we observed sex effects on EEG power. FPT did not eliminate the genotype difference in relative gamma power from the LSSC. FPT, however, robustly decreased relative alpha power in the LSSC and auditory cortex, with more pronounced effects in Fmr1 KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only in Fmr1 knockout mice. FPT also increased relative delta power, with more pronounced effects in Fmr1 KO mice and caused small but significant increases in relative beta power. Distinct impacts of FPT on cortical EEG were like effects caused by certain FDA-approved psychotropic medications (including baclofen, allopregnanolone, and clozapine). These results advance the understanding of FPT's pharmacological and neurophysiological effects.
Keywords: 5-HT1; EEG; Fmr1; alpha power; delta power; gamma power; serotonin.
Conflict of interest statement
The authors declare no competing financial interest.
Figures
![Figure 1.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10364582/bin/nihms-1913018-f0002.gif)
![Figure 2.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10364582/bin/nihms-1913018-f0003.gif)
![Figure 3.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10364582/bin/nihms-1913018-f0004.gif)
![Figure 4.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/10364582/bin/nihms-1913018-f0005.gif)
Similar articles
-
Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice.Neuropharmacology. 2024 Mar 1;245:109774. doi: 10.1016/j.neuropharm.2023.109774. Epub 2023 Nov 3. Neuropharmacology. 2024. PMID: 37923121
-
(S)-5-(2'-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder.ACS Pharmacol Transl Sci. 2020 Feb 21;3(3):509-523. doi: 10.1021/acsptsci.9b00101. eCollection 2020 Jun 12. ACS Pharmacol Transl Sci. 2020. PMID: 32566916 Free PMC article.
-
Sensory Processing Phenotypes in Fragile X Syndrome.ASN Neuro. 2018 Jan-Dec;10:1759091418801092. doi: 10.1177/1759091418801092. ASN Neuro. 2018. PMID: 30231625 Free PMC article. Review.
-
Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome.Neurobiol Dis. 2016 May;89:126-35. doi: 10.1016/j.nbd.2016.02.002. Epub 2016 Feb 2. Neurobiol Dis. 2016. PMID: 26850918 Free PMC article.
-
BDNF in fragile X syndrome.Neuropharmacology. 2014 Jan;76 Pt C:729-36. doi: 10.1016/j.neuropharm.2013.05.018. Epub 2013 May 29. Neuropharmacology. 2014. PMID: 23727436 Review.
Cited by
-
Development of 2-Aminotetralin-Type Serotonin 5-HT1 Agonists: Molecular Determinants for Selective Binding and Signaling at 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F Receptors.ACS Chem Neurosci. 2024 Jan 17;15(2):357-370. doi: 10.1021/acschemneuro.3c00658. Epub 2023 Dec 27. ACS Chem Neurosci. 2024. PMID: 38150333 Free PMC article.
-
The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors.ACS Pharmacol Transl Sci. 2023 Sep 18;6(10):1480-1491. doi: 10.1021/acsptsci.3c00137. eCollection 2023 Oct 13. ACS Pharmacol Transl Sci. 2023. PMID: 37854624
-
Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.Int J Mol Sci. 2023 Sep 22;24(19):14460. doi: 10.3390/ijms241914460. Int J Mol Sci. 2023. PMID: 37833907 Free PMC article.
-
Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors.ACS Chem Neurosci. 2023 May 17;14(10):1884-1895. doi: 10.1021/acschemneuro.3c00148. Epub 2023 Apr 27. ACS Chem Neurosci. 2023. PMID: 37104867 Free PMC article.
References
-
- Van der Aa N; Kooy RF GABAergic abnormalities in the fragile X syndrome. Eur. J. Paediatr Neuro 2020, 24, 100–104. - PubMed
-
- Kang Y; Zhou Y; Li Y; Han Y; Xu J; Niu W; Li Z; Liu S; Feng H; Huang W; Duan R; Xu T; Raj N; Zhang F; Dou J; Xu C; Wu H; Bassell GJ; Warren ST; Allen EG; Jin P; Wen Z A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies. Nature Neuroscience 2021, 24, 1377–1391. - PMC - PubMed
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials