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Novel Triple Uptake Inhibitors for Treatment of Depression

用于治疗抑郁症的新型三重摄取抑制剂

基本信息

批准号：
8259537
负责人：
Aloke K Dutta
金额：
$ 38.39万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-03 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259537
关键词：
Acute Address Adolescent Adverse effects Affinity Aftercare Anhedonia Animal Experiments Animal Model Anti-Anxiety Agents Antidepressive Agents Biochemical Biological Availability Brain-Derived Neurotrophic Factor Cardiovascular Diseases Cell Line Chronic Clinic Clinical Data Depressed mood Development Disease Disease remission Dopamine Dose Drug Kinetics Enrollment Exhibits Goals Health Hippocampus (Brain)Human Cloning In Vitro Individual Isomerism Label Lead Life Locomotion Major Depressive Disorder Measures Mental Depression Methods Mind Modeling Modification Molecular Motor Activity Mus Nature Norepinephrine Pathway interactions Patients Pharmacotherapy Production Property Pyrans Rattus Refractory Relapse Rewards Role Selective Serotonin Reuptake Inhibitor Serotonin Structure-Activity Relationship Swimming System Tail Suspension Testing Unipolar Depression base depressive symptoms design dopamine transporter fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether follow-up frontal lobe functional group improved in vitro testing in vivo inhibitor/antagonist monoamine noradrenaline transporter norepinephrine system novel pharmacophore piperidine research study response reuptake serotonin transporter suicidal act suicide rate tool transmission process uptake

项目摘要

Dutta, Aloke K Major depression disorder is a significant health problem and behind the cardiovascular disease, depression is considered as the second most debilitating disease in the world. Selective serotonin reuptake inhibitors (SSRIs) antidepressant agents have been limited by slow onset of action and also have been implicated recently in high adolescent suicide rate and other side effects. In spite of developments of different array of antidepressants, there still remains a significant unmet need for much more improved therapy, as large numbers of depressed people are still refractory to the current existing therapies. Ironically, in the current pharmacotherapy of depression, dopaminergic component has not been included when there are ample clinical and biochemical evidences pointing towards a strong dopaminergic component in depression. Recently, triple monoamine uptake inhibitors (TUI) interacting with dopamine, serotonin and norepinephrine transporters have been implicated in potent antidepressant activity. This is due to the fact that additional dopaminergic component can effectively relieve depression by activating mesocorticolimbic dopaminergic pathways in the reward system. This can act to reduce anhedonia, which is associated with a deficit in dopaminergic transmission and is a central component to a depressive state of mind. In our effort to discover and develop novel molecules for interaction with multiple monoamine transporters, we have recently developed asymmetric di- and tri- substituted pyran derivatives. Uptake inhibition studies with all three monoamine transporters indicated variety of activities depending upon the nature of substitutions either on the pyran ring or on the N-benzyl moiety. The preliminary results also indicated stereospecific requirement for interaction of these molecules with the monoamine transporters as the potent interaction was mostly exhibited in the (-)-isomers. Three different classes of molecules emerged from these studies and they are labeled as serotonin-norepinephrine reuptake inhibitors (SNRI), NRI and triple reuptake inhibitors (TUI). One of the lead TUI molecules, (-)-17a, exhibiting potent norepinephrine and serotonin inhibition (Ki; 5.09 and 37.7 nM, respectively) activity along with modest dopamine transporters uptake inhibition activity (Ki; 85 nM), was further evaluated in different in vivo depression animal model studies. In vivo results indicated (-)-17a could potently reduce immobility in rat forced swimm test and mice tail suspension test. Furthermore, locomotor activity results indicated that this reduction of immobility was not due to locomotor activation. We now plan to follow up on our preliminary SAR studies on these pyran derivatives to develop more suitable TUI lead molecules. Lead compounds with suitable properties will be evaluated for antidepressant properties in animal experiments. Two most potent antidepressant molecules will be tested for their antianxiety effect and also on expression of brain derived neurotrophic factor (BDNF), implicated in the clinical action of antidepressant drugs.

Dutta, Aloke K