This application, "Novel serotonergic, pro-cognitive antipsychotic therapies", is in response to PA-08-142: "Pharmacologic Agents and Drugs for Mental Disorders" (SBIR [R43/R44]). Schizophrenia is a devastating brain disorder that affects approximately 0.7% of the global population. The symptoms of schizophrenia can be grouped into three major categories: positive (e.g. hallucinations and delusions), negative (e.g. social isolation and inappropriate emotional response), and cognitive symptoms. The cognitive symptoms of schizophrenia include impaired attention and disruption of working memory, an essential type of short term memory. These fundamental cognitive processes are critical for the performance of day-to-day activities, and their disruption in schizophrenia is a key factor underlying the inability of patients to integrate successfully into society. Indeed, the cognitive deficits associated with schizophrenia are recognized as a core component of the disorder. Currently available antipsychotic therapies are effective at ameliorating the positive symptoms of schizophrenia, but they are not effective at treating the negative or cognitive symptoms of the disease. Moreover, these therapies often cause significant side effects such as motor disturbances, weight gain, and diabetes. For these reasons, schizophrenia represents a major area of unmet medical need which must be addressed by the discovery and development of new antipsychotic therapies that are effective at treating the cognitive symptoms of schizophrenia with reduced potential for side effects. The overall goal of this proposal is to optimize a series of lead compounds we have identified with dual 5-HT2C receptor agonist and 5-HT6 receptor antagonist activities. Compounds with this novel pharmacological profile hold promise for yielding safe and effective treatments for the positive as well as the cognitive symptoms of schizophrenia. Such compounds are likely to have a significantly reduced risk for generating the undesirable side effects that are typically observed with currently available antipsychotic therapies. Successful completion of the specific aims outlined in this proposal will result in the identification of lead compounds with desirable pharmacological and drug-like properties. Furthermore, proof-of-concept for this novel target profile will be achieved by demonstrating antipsychotic and pro-cognitive efficacy in animal models with a selected lead compound. These achievements will provide a solid basis for a Phase II SBIR application to support further research aimed at selecting a clinical development candidate for the treatment of schizophrenia and its cognitive symptoms. A clinical development candidate with this novel profile would comprise a valuable asset within the pharmaceutical industry and would provide the basis of a successful commercial outcome for the research program. The research outlined in this proposal will directly benefit patients and their families and caregivers by leading to the discovery of safer and more effective medicines for the treatment of schizophrenia.
Public Health Relevance: We have discovered a series of compounds with a unique target profile for specific serotonin receptors that are relevant to schizophrenia and cognition. Based on this discovery, we are optimizing these compounds to identify a new class of candidate drugs for treatment of schizophrenia and its severe cognitive deficits. Our goal is to discover new therapies that are more effective than current treatments with reduced potential for side effects. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.
Thesaurus Terms: 4h-Dibenzo(De,G)Quinoline-10,11-Diol, 5,6,6a,7-Tetrahydro-6-Methyl-, (R)-;5-Ht Receptors;5-Ht(2c) Receptor;5-Ht-2a Gene;5-Ht2a;5-Ht2c Receptor;5-Ht6 Receptor;5-Hydroxytryptamine (Serotonin) Receptor 2a Gene;5-Hydroxytryptamine Receptor 2a Gene;5-Hydroxytryptamine Receptors;5-Hydroxytryptamine Type 2c Receptors;Achievement;Achievement Attainment;Address;Adverse Effects;Affect;Affinity;Agonist;Animal Model;Animal Models And Related Studies;Antipsychotic Agents;Antipsychotic Drugs;Antipsychotics;Apomorphine;Appetite;Area;Associative Learning;Attention;Brain Diseases;Brain Disorders;Brain Region;Categories;Cell Communication And Signaling;Cell Signaling;Characteristics;Chemicals;Chronic;Clinical;Cognition;Cognitive;Cognitive Manifestations;Cognitive Symptoms;Cognitive Deficits;Common Rat Strains;D2 Receptor;Drd2 Receptor;Delusions;Desire For Food;Development;Diabetes Mellitus;Disease;Disorder;Dopamine D2 Receptor;Drug Industry;Drug Kinetics;Drugs;Emotional;Encephalon Diseases;Family Care Giver;Family Caregiver;Family Member;Glutamates;Goals;Htr2;Htr2 Gene;Htr2a;Htr2a Gene;Hallucinations;Human;Immediate Memory;Impairment;In Vitro;Indoles;Intracellular Communication And Signaling;Intracranial Cns Disorders;Intracranial Central Nervous System Disorders;L-Glutamate;Loinc Axis 2 Property;Lead;Learning;Major Tranquilizers;Major Tranquilizing Agents;Man (Taxonomy);Medical;Medication;Medicine;Memory;Mental Disorders;Mental Health Disorders;Modern Man;Motor;Nerve Impulse Transmission;Nerve Transmission;Neurobehavioral Manifestations;Neurobehavioral Signs And Symptoms;Neuroleptic Agents;Neuroleptic Drugs;Neuroleptics;Neuronal Transmission;Outcome;Outcomes Research;Pathway Interactions;Patients;Pavlovian Conditioning;Pb Element;Performance;Performance At Work;Pharmaceutic Industry;Pharmaceutic Preparations;Pharmaceutical Industry;Pharmaceutical Preparations;Pharmacokinetics;Phase;Physiologic Pulse;Population;Position;Positioning Attribute;Pre-Clinical Model;Preclinical Models;Process;Property;Psychiatric Disease;Psychiatric Disorder;Psychoses;Psychotic Disorders;Pulse;Rat;Rats Mammals;Rattus;Receptor, Serotonin, 5-Ht2c;Refractory;Regulation;Research;Risk;Sbir;Sbirs (R43/44);Schizophrenia;Schizophrenic Disorders;Series;Serotonin 2c Receptor;Serotonin 5-Ht-2 Receptor Gene;Short-Term Memory;Shortterm Memory;Signal Transduction;Signal Transduction Systems;Signaling;Small Business Innovation Research;Small Business Innovation Research Grant;Social Isolation;Societies;Solid;Staging;Symptoms;Testing;Therapeutic;Treatment Side Effects;Weight Gain;Weight Increase;Atypical Antipsychotic;Base;Biological Signal Transduction;Body Weight Gain;Body Weight Increase;Cholinergic;Classical Conditioning;Dementia Praecox;Design;Designing;Developmental;Diabetes;Disease/Disorder;Drug Candidate;Drug/Agent;Effective Therapy;Effective Treatment;Efficacy Evaluation;Glutamatergic;Heavy Metal Pb;Heavy Metal Lead;Improved;In Vivo;Job Performance;Lead Series;Meetings;Mental Illness;Model Organism;Neurotransmission;New Approaches;New Therapeutic Approach;New Therapeutic Intervention;Novel;Novel Approaches;Novel Strategies;Novel Strategy;Novel Therapeutic Approach;Novel Therapeutic Intervention;Object Recognition;Pathway;Prevent;Preventing;Programs;Psychological Disorder;Response;Scaffold;Scaffolding;Schizophrenic;Serotonin Receptor;Side Effect;Stereotypy;Therapeutic Target;Therapy Adverse Effect;Treatment Adverse Effect;Work Performance;Working Memory;Wt Gain
