Catatonia is a widespread and serious syndrome characterized by mutism, stupor, refusal to eat or drink, posturing, and hypokinesis, and affects a broad range of psychiatric and other patients in the US and worldwide. Untreated or poorly managed catatonic patients suffer from a wide range of ailments including bed sores, deep venous thrombi, pulmonary emboli, urinary retention, infection, and aspiration pneumonia, which can lead to severe medical impairment and death. Existing treatments for catatonia including lorazepam (a benzodiazepine) often require high doses for an effective response, some patients are unresponsive, and chronic catatonia is poorly controlled. Discovery of a new treatment for catatonia would have a considerable commercial and scientific value. Our approach is to target an orphan drug receptor present in the cerebellum that is preferentially activated by lorazepam. We propose to carry out a Structure-Activity Relationship (SAR) program of synthesis and biological evaluation of specifically designed lorazepam derivatives. From this project we specifically aim to discover one or more benzodiazepine analogs showing the desired in vitro orphan drug receptor potency and selectivity. In Phase Two compounds with a promising in vitro profile will be examined in vivo in knockout mice to confirm their mode of action. The best lead compounds will be further optimized and then evaluated in an animal model for catatonia. The long- term goal of this project is to discover a new, improved pharmaceutical agent for treatment of catatonia that can be licensed and developed for ultimate market approval.
Public Health Relevance: Catatonia is a serious health problem in the Unites States, and the existing drug treatments are not always effective and have side effects. We are carrying out research to discover and develop a new drug to help these patients. If we are successful, doctors will have another option to help sufferers of catatonia.
Thesaurus Terms: 2h-1,4-Benzodiazepin-2-One, 7-Chloro-5-(2-Chlorophenyl)-1,3-Dihydro-3-Hydroxy-;5-Ht Agonists;5-Hydroxytryptamine Agonists;5-Hydroxytrytamine Agonist;Abc20;Abcb1;Abcb1 Gene;Atp-Binding Cassette, Sub-Family B (Mdr/Tap), Member 1 Gene;Achievement;Achievement Attainment;Active Sites;Acute;Adverse Effects;Affect;Agonist;Animal Model;Animal Models And Related Studies;Anti-Anxiety Agents;Anti-Anxiety Drugs;Anticonvulsant Agent;Anticonvulsant Drugs;Anticonvulsants;Anticonvulsive Agents;Anticonvulsive Drugs;Anxiolytic Agents;Anxiolytics;Apoplexy;Aspiration Pneumonia;Ativan;Autoimmune Diseases;Bed Sores;Bedsore;Benzodiazepine Compounds;Benzodiazepine Receptor;Benzodiazepines;Biological;Bipolar Affective Psychosis;Bipolar Disorder;Brain Inflammation;Brain Vascular Accident;Butanoic Acids;Butyric Acids;Catatonia;Cell Nucleus;Cerebellum;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Cessation Of Life;Chronic;Clinical;Collaborations;Computer Assisted;Death;Decubitus Ulcer;Development;Diazepam Receptors;Docking;Dose;Drug Receptors;Drug Screening;Drugs;Eating;Electroconvulsive Shock;Electroshock;Embolism;Embolus;Encephalitis;Evaluation;Evaluation Studies, Drug, Pre-Clinical;Evaluation Studies, Drug, Preclinical;Exhibits;Food Intake;G Protein-Coupled Receptor 68;G Protein-Coupled Receptor, Family C, Group 5, Member C;G Protein-Coupled Receptor, Family C, Group 5, Member C, Human;Gp170;Gpr68;Gpr68 Gene;Gated Ion Channel;Goals;Grant;Health;History;Human;Impairment;In Vitro;Infection;Inpatients;Intellectual Property;Knock-Out Mice;Knockout Mice;Lead;Legal Patent;Licensing;Ligands;Lorazepam;Lung;Lung Respiratory System;Mdr-1;Mdr1;Mdr1 Gene;Man (Taxonomy);Manic-Depressive Psychosis;Marketing;Mediating;Medical;Medication;Minor Tranquilizing Agents;Modern Man;Modification;Molecular;Multidrug Resistance Gene-1;Multidrug Resistance Gene-1s;Muscle Relaxants;Mutism;Nimh;National Institute Of Mental Health;National Institute Of Mental Health (U.S.);North Carolina;Nucleus;Null Mouse;Ogr-1;Ogr1;Obtundation;Orphan Drugs;Orphan G-Protein Coupled Receptor;Ovarian Cancer G Protein-Coupled Receptor 1;P-Gp;P-Glycoprotein 1 Gene;Pgy1;Patents;Patients;Pattern;Pb Element;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Posture;Preclinical Drug Evaluation;Pressure Sore;Pressure Ulcer;Psychoactive Agents;Psychoactive Compound;Psychoactive Drugs;Psychopharmaceuticals;Psychotropic Drugs;Receptor Protein;Recording Of Previous Events;Research;Research Resources;Resources;Retinoic Acid Responsive Gene Protein;Sbir;Sbirs (R43/44);Schizophrenia;Schizophrenic Disorders;Sedation Procedure;Serotonergic Agonists;Serotonin Agonists;Serotonin Receptor Agonists;Site;Small Business Innovation Research;Small Business Innovation Research Grant;Sphingosylphosphorylcholine Receptor;Structure;Structure-Activity Relationship;Stupor;Syndrome;Testing;Thrombus;Treatment Side Effects;United States;Universities;Urinary Retention;Venous;Work;Analog;Antianxiety Agent;Autoimmune Disorder;Base;Bipolar Affective Disorder;Brain Attack;Cerebral Vascular Accident;Cerebrovascular Accident;Chemical Structure Function;Computer Aided;Dementia Praecox;Design;Designing;Developmental;Drinking;Drug Development;Drug/Agent;Functional Group;Heavy Metal Pb;Heavy Metal Lead;Human G-Protein-Coupled Receptor 68;Human Gpr68 Protein;Human Gprc5c Protein;Human Ogr1 Protein;Human Raig-3 Protein;Improved;In Vivo;Interest;Manic Depressive Disorder;Manic Depressive Illness;Model Organism;Neuropsychiatric;Neuropsychiatry;Novel;Programs;Pulmonary;Receptor;Respiratory;Response;Schizophrenic;Sedation;Side Effect;Stroke;Structure Function Relationship;Therapy Adverse Effect;Treatment Adverse Effect
