NMDA receptor NR2D subtype-selective allosteric modulator for the treatment of im

DESCRIPTION (provided by applicant): This is an SBIR Phase I proposal is to test the feasibility of developing drug-like small molecules that are positive allosteric modulators of the NR2D subtype of the NMDA receptor (NR2D PAMs) for the purpose of treating impulsivity disorders, notably ADHD. The prevalence of ADHD in both children and adults is estimated at 4-5%. This disorder is treated with behavioral therapy and/or drugs; however, about 80% of patients continue to present with an unmet medical need. Toaddress this need, we are developing NR2D PAMs. The subthalamic nucleus (STN) is a brain region that plays a key role in controlling impulsivity. Low neuronal activity in the STN is associated with impulsivity, whereas increased neuronal activity is associated with decreased impulsivity. Therefore, a drug that selectively increases neuronal activity in the STN may offer a new approach for treating ADHD. The NR2D subtype is the main NMDA receptor present in the STN and this receptor subtype is only highly expressed in the STN. Drugs that selectively potentiate NR2D receptors are likely to increase neuronal activity in the STN and decrease impulsive behaviors, while minimizing side effects by avoiding NMDA subtypes in other parts of the brain. Molecules thatcan potentiate NR2D receptors have been reported. However, these compounds lack sufficient potency and pharmaceutical properties to be suitable drug candidates. The goal of this proposal is to test the feasibility of developing NR2D PAMs that have suitabledrug like properties and establish their therapeutic potential by demonstrating efficacy in an animal model of impulsive behavior (the five choice serial reaction time task or 5-CSRTT) that is used industry wide for screening drugs to treat such disorders. To this end, we will undertake an iterative medicinal chemistry program to improve NR2D PAMs for in vivo testing in the 5-CSRTT model of impulsive behavior. Test of Feasibility: the following conditions must be met for feasibility to be shown: 1. NR2Dpotentiation ED50 lt 100 nM; selectivity for NR2D over NR2A-C gt 20 fold 2. MW lt 500, clogP 1 to 5, H-bond donors lt 5; polar surface area 25-100 2 3. Permeability in Caco-2 gt 5 cm x 10-6/sec; Protein binding lt 99%; asymmetry in MDR1-transfected MDCK cell lines lt 2.5 4. Terminal plasma half-life in rat gt 1 h after subcutaneous administration, brain/plasma ratio gt 0.5, peak free plasma level gt 3 X EC50 for NR2D potentiation between 30-60 min post-dose. 5. Dose-dependent inhibition of dopamine D1 agonist-induced locomotor activity 6. Inhibition by 50% of premature responding in the 5-CSRTT. If Phase I is successful, we will apply for Phase II funds to further develop lead compounds and conduct more extensive in vivo efficacy testing that may lead to the filing of an IND. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The prevalence of ADHD in both children and adults is estimated at 4-5%. This disorder is treated with behavioral therapy and/or drugs; however, about 80% of patients continue to present with an unmet medical need. This is a proposal to develop a drug that works by a new mechanism to address this condition more effectively and with fewer unwanted side effects.