The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines Autism Spectrum Disorder with two main domains: communication and language deficits, and repetitive behaviors and restricted interests. The frequency and degree of severity of these repetitive behaviors vary from one individual to another and negatively affect the individual's social and educational experience, and impair the quality of life of the individual and the community as a whole.<br/><br/>Increasing the level of serotonin in the synaptic cleft is capable of relieving/modulating some of these disruptive behaviors via an unknown mechanism. As such, Selective Serotonin Reuptake Inhibitors (SSRIs), a drug class that block the uptake of serotonin, would be an ideal choice. However, the elevated level of serotonin (by SSRIs) also stimulates inhibitory autoreceptors to exert a negative feedback inhibition, and counteract the action of SSRIs. Therefore, it takes 4-6 weeks to SSRIs to become therapeutically efficient, which might be attributed to the time needed for serotonin autoreceptor to be desensitized. Acute blockade of autoreceptors eliminates their negative feedback effect and increases the efficiency of SSRIs.<br/><br/>This established synergistic activity motivated us to incorporate SSRIs and autoreceptor antagonists in a series of bi-functional ‘hybrids’ to achieve rapid and consistent increase in serotonin concentration and a corresponding quick control over the disruptive repetitive symptoms. Two series of compounds have been designed in our lab to test the two in one approach: fluoxetine derived series and sertraline derived series. We use the tethering technique in our design, and all of our compounds include N-arylpiperazines as a common motif. Of the more than 25 new compounds that have been synthesized and tested, 2 molecules displayed 100% inhibition at both serotonergic targets. The detailed synthetic scheme of both series, the corresponding biological data including the inhibition concentration (IC50), and a comparison of the two series will be presented.

Two-in-one approach to modulate repetitive behaviors in autism spectrum disorder: N-arylpieprazines as key motifs towards developing bi-functional serotonergic ligands

253rd National Meeting (2017)

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