Selective Serotonin Reuptake Inhibitors (SSRIs) with Dual Functionality; Hybrid Anti-Autism Candidates

Abstract

Autism is a lifelong neurodevelopmental disorder significantly on the rise worldwide. Prevalence rate increased dramatically from 1 case/10000 in the early 90's to 1 case/110 in 2011. The diagnosis is characterized by three main domains: dysfunction in social interaction, communication impairment and repetitive behaviors. Selective Serotonin Reuptake Inhibitors (SSRIs) are currently the drug class of choice for treating autism symptoms. The major drawback of SSRIs is that they take several weeks to become therapeutically efficient. Co-administration of SSRIs with 5-HT1B/1D receptor antagonists proved to be advantageous over SSRIs alone with respect to the magnitude of brain serotonin levels produced. The theory is that the acute blockade of 5-HT1B/1D receptor would prevent the negative feedback these autoreceptors exert normally on serotonin release and hence enhance the efficiency of SSRIs (i.e. synergistic effect). We hypothesize to incorporate the dual pharmacophoric profile of serotonin reuptake inhibition and 5-HT1B/1D antagonism in one single molecule carrying dual functionalities. A library of 12 virtual hybrids was successfully designed. The organic synthesis of two chosen hybrids was completed with full structure elucidation, including elemental analysis and proton-Nuclear Magnetic Resonance. The main outcome of the study is obtaining an unprecedented library of novel hybrid molecules combining serotonin reuptake inhibition with 5HT1B/1D antagonism in one single molecule. In addition, establishing chemical synthesis and other foundation materials needed for further investigation (In vitro and in vivo pharmacological evaluation) towards our ultimate goal of developing new therapeutic line of autism, where no other lines of treatment have been consistently successful.