SAR of Phenoxyacetic Acid Analogs As Synergistic Dual Activity Serotonergic Ligands for Potential Use in ASD

Saturday, May 14, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
L. Tran1, O. M. Ghoneim1 and A. A. Khalil2, (1)University of Saint Joseph School of Pharmacy, Hartford, CT, (2)Qatar University-College of Pharmacy, Doha, Qatar

Repetitive/stereotypic behaviors are one of Autism Spectrum Disorder’s (ASD) main domains and include persistent preoccupation with an object, phrase, or body movement that hampers educational or social interventions, and creates disturbance in the life of individuals and their caregivers. Currently, Selective Serotonin Reuptake Inhibitors (SSRIs) are used as first-line treatment for Obsessive-Compulsive Disorder and have been successfully used to treat repetitive behaviors in ASD individuals. SSRIs inhibit serotonin (5-HT) reuptake by blocking the serotonin transporter on the presynaptic neuron, as a way to increase synaptic serotonin. Another pathway to increase serotonin levels is to manipulate serotonin autoreceptors such as 5-HT1A, 5-HT1B, and 5-HT1D receptors by regulating the synthesis of serotonin in the synapse based on demand. Accordingly, high 5-HT level in the synaptic cleft (enhanced by SSRIs) will stimulate the autoreceptors to decrease 5-HT synthesis and therefore counteract SSRIs. As a result, the 4-6 week delay in the therapeutic effect of SSRIs may be attributed to the time needed for the 5-HT autoreceptor to be desensitized. Co-administration of SSRIs with 5-HT autoreceptor antagonists is advantageous over SSRIs alone with respect to the magnitude of extracellular brain 5-HT levels produced. Encouraged by this fact, our laboratory has been investigating the combination of 5-HT uptake inhibition and autoreceptor antagonism in one molecule to act as synergistic dual-activity serotonergic ligand.

The design of the dual functional ligand comprises of structural features responsible for serotonin reuptake inhibition derived from fluoxetine (blue side; Figure 1) tethered to structural features responsible for autoreceptor inhibition from the non-selective autoreceptor antagonist GR-127935 (red side; Figure 1). Two compounds that provide proof of our pharmacologic concept include, OG-103 and JDO-106 as in vitro dual functional serotonergic ligands. Both compounds achieved 90-100% inhibition of 5-HT uptake when tested at 10 μM concentrations, which indicates activity from the blue side. However, their effect on 5-HT autoreceptor antagonism varied, indicating improvements can be made to the autoreceptor inhibition component.


Establish a structure activity relationship (SAR) of these fluoxetine-derived compounds called the LG-series, to achieve lead compound(s) that can effectively inhibit 5-HT uptake and antagonize 5-HT autoreceptors concomitantly.  


We used a four-step synthetic scheme. Briefly, a Williamson ether synthesis of trifluoromethylphenol and methyl-bromophenylacetate provided the ester core, followed by hydrolysis to yield the substituted phenoxyacetic acid. Coupling the acid with varying amines/anilines resulted in the wide varieties within the LG-series. 


Eleven final compounds were synthesized in our laboratory from the LG-series encompassing amines/aniline of diverse steric and electronic characteristics. The biological screening of the LG-series was conducted at Eurofins/CEREP, Inc. The synthetic scheme, reaction conditions, and the effect of the various amines on the inhibition of the 5-HT uptake and serotonin autoreceptors will be presented.


Our findings suggest that phenoxyacetic acid analogs can be used as a potential new class of agents with synergistic dual activity serotonergic ligands for repetitive behaviors modulation in ASD.