FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT_1A, 5-HT_1B, and 5-HT_1D 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 restingstate 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-HT 1A , 5-HT 1B , and 5-HT 1D Rs, 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,Ndimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT 1A Rs and a potent, low-efficacy partial agonist at 5-HT 7 Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT 1B and 5-HT 1D Rs. FPT's K i values at 5-HT 1B and 5-HT 1D Rs were <5 nM, but it had nil activity (>10 μM K i ) at 5-HT 1F Rs. 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.

Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors

“…Due to its high potency at the α2AR juxtaposed against inverse agonist activity at the α2CR, as well as its encouraging performance in mouse models of autism − and ongoing use in studies in nonhuman primates, FPT was selected for further analysis in molecular modeling studies in order to elucidate the molecular determinants for binding and function at the α2AR and α2CR.…”

“…The 5- s ubstituted-2-dimethyl a mino t etralin (5-SAT, Table ) chemotype is a novel scaffold synthesized in our lab that has neurotherapeutic activities in mouse models . In particular, the 5-SAT FPT (Table ) is an orally active analogue that improves repetitive behaviors, social behaviors, anxiety behaviors, and ameliorates seizures in mouse models of autism spectrum disorder (ASD), − which often is comorbid with ADHD . Importantly, FPT did not impact locomotor activity in rodents, suggesting there may not be sedative effects and/or abuse liability.…”

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

“…We designed and synthesized new 5-SATs to exploit the results obtained from experimental and computational studies herein and realized a new full efficacy 5-HT 1A agonist ( FPIP ) with 100-fold selectivity over 5-HT 1B and 5-HT 1D receptors. We will continue efforts to develop highly selective ligands for 5-HT 1B as well as 5-HT 1D receptors using the 5-SAT platform given the chemotype, as represented by (2 S )- FPT , appears to be safe as well as effective, for example, in animal models of substance use disorder as well as autism and fragile X syndrome. − …”

“…Cell Culture techniques followed procedures previously published by our lab. ,,,, Briefly, HEK293T cells were obtained from ATTC (Manassas, VA) and cultured in DMEM supplemented with 10% regular FBS (%v/v) and 1% penicillin (%v/v) at 37 °C in a humidified incubator kept at 5% CO 2 . Cells were passaged at 80% confluency up until passage 20.…”

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

“…We have been researching 5-HTRs as targets for treating FXS and ASD. − FXS is a monogenic neurodevelopmental disorder that is the leading cause of intellectual disability and ASD . In addition to various other neurobehavioral issues, individuals with FXS present with auditory hypersensitivities and seizures .…”