FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT, 5-HT, and 5-HT Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Knockout Mice.

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 knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT, 5-HT, and 5-HTRs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects in knockout mice of an orally active 2-aminotetralin, ()-5-(2'-fluorophenyl)-,-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HTRs and a potent, low-efficacy partial agonist at 5-HTRs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT and 5-HTRs. FPT's values at 5-HT and 5-HTRs were <5 nM, but it had nil activity (>10 μM ) at 5-HTRs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adult knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and female 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 KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only in knockout mice. FPT also increased relative delta power, with more pronounced effects in 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.