Novel treatment of posttraumatic stress disorder

DESCRIPTION provided by applicant The present application andquot Novel Treatment for Posttraumatic Stress Disorderandquot addresses the critical need for efficacious treatments for posttraumatic stress disorder PTSD A key neural signaling cascade activated by a trauma experience is initiated by the excitatory neurotransmitter glutamate Activation of the NMDA receptor a glutamate receptor subtype results in subsequent activation of the enzyme neuronal nitric oxide synthase nNOS and ultimately an increase in the production of the signaling molecule nitric oxide NO These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD Postsynaptic density protein PSD targets nNOS to the NMDA receptor and is therefore required for NMDA receptor activation of nNOS Dr Lai Principal investigator for this project first showed that the small molecule inhibitor IC disrupts the functional protein protein interaction between nNOS and PSD in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo Our preclinical team led by Dr Shekhar Founder of Anagin has now shown that IC and a related analog ZL block the long term encoding of conditioned fear even after a fear conditioning session has occurred i e post trauma Unlike NMDA receptor antagonists these protein interaction inhibitors are efficacious without impairing motor movement or memory Thus disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side effects We have assembled a collaborative team with synergistic and complementary expertise to unite extensive combined experience in drug discovery Lai development of novel preclinical stress and memory models Shekhar and Hohmann chemical optimization of lead compounds Thakur and target validation Lai and Hohmann to conduct work proposed under two Specific Aims Aim of this proposal will characterize the pharmacokinetic profile and oral efficacy of our lead inhibitors Aim will then use a traditional drug medicinal chemistry approach to design and develop a back up chemical series with improved solubility and potency compared to the parent compounds Results from this SBIR Phase I study will lay the foundation for further lead optimization and preclinical development of nNOS targeting inhibitors as novel treatments for PTSD in Phase II These studies are expected to validate the disruption of signal protein compartmentalization as an innovative and feasible approach to drug development The development of effective pharmacotherapies with novel chemical structures that possess limited side effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients PUBLIC HEALTH RELEVANCE Posttraumatic distress disorder PTSD is a highly prevalent disabling condition for which effective therapies are still lacking resulting in significant suffeing and socioeconomic burden This proposal seeks to develop novel small molecule inhibitors that specifically disrupt a major neuronal signaling pathway implicated in persistence of PTSD symptoms The proposed studies will characterize the preclinical efficacy of these inhibitors and develop novel analogs based on our initial chemical leads