(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

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow association and rapid dissociation kinetics at 5-HT2CRs. Finally, we reassessed and report FPT’s affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.

Serotonin Receptors as Therapeutic Targets for Autism Spectrum Disorder Treatment

“…Moreover, the authors pursued thorough pharmacokinetic study and claimed that orally operative (+)-5-FPT appears to be a promising candidate for ASD treatment. The group re-evaluated pharmacokinetic values and further validated the effect of (+)-5-FPT in a genetic model, Fmr1 knockout, and wild-type mice [ 102 ]. In addition to providing anxiolytic-like effects, it significantly relieved repetitive behavior and enhanced social interaction both in wild-type and the transgenic mice.…”

Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor

“…Taking all the following evidence into consideration, there is a strong demand for the development of novel 5-HT7R agonists with improved pharmacokinetic properties and activity. Armstrong and co-workers recently reported that treatment with the orally operative aminotetraline compound (+)-5-FPT [ 65 ], which is a partial agonist of 5-HT1A, 5-HT2C, and 5-HT7 receptors, leads to significant improvement in the phenotypic condition [ 78 ] ( Table 1 ). In particular, it considerably mitigated repetitive behavior, markedly reduced the occurrence of lethal audiogenic seizures, which are typical for Fmr1-KO condition, and elevated the social activity both in wild-type and FXS transgenic mice [ 78 ].…”

“…Armstrong and co-workers recently reported that treatment with the orally operative aminotetraline compound (+)-5-FPT [ 65 ], which is a partial agonist of 5-HT1A, 5-HT2C, and 5-HT7 receptors, leads to significant improvement in the phenotypic condition [ 78 ] ( Table 1 ). In particular, it considerably mitigated repetitive behavior, markedly reduced the occurrence of lethal audiogenic seizures, which are typical for Fmr1-KO condition, and elevated the social activity both in wild-type and FXS transgenic mice [ 78 ]. As well as 5-HT 1A R, 5-HT 2C R was shown to be involved in the activation of phospholipase C beta (PLCβ), protein kinase C (PKC), and, as a consequence, the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK/MAPK) signaling pathway, which is essential for normal cell functioning, and its alteration is detected in various neurological disorders [ 85 , 86 , 87 ].…”

Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder

“…The (+)-5-FPT potently attenuated stereotypy in three heterogeneous models of stereotypy in a mouse strain characterized by repetitive behavior . In 2020, the same research group reported that (+)-5-FPT was actually a 5-HT 1A R/5-HT 2C R agonist and 5-HT 7 R antagonist . This compound was then studied in a mouse model of Fragile X syndrome and found to reduce repetitive behavior through 5-HT 1A R partial agonism and to attenuate audiogenic seizure through 5-HT 2C R agonism.…”

“…26 In 2020, the same research group reported that (+)-5-FPT was actually a 5-HT 1A R/5-HT 2C R agonist and 5-HT 7 R antagonist. 27 This compound was then studied in a mouse model of Fragile X syndrome and found to reduce repetitive behavior through 5-HT 1A R partial agonism and to attenuate audiogenic seizure through 5-HT 2C R agonism. Thus, the potential of concomitant activation of 5-HT 1A R and 5-HT 7 R was not actually explored.…”