Repositioning Candidate Details
| Candidate ID: | R0161 |
| Source ID: | DB00476 |
| Source Type: | approved |
| Compound Type: | small molecule |
| Compound Name: | Duloxetine |
| Synonyms: | (3S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-amine; (S)-duloxetine; Duloxetine |
| Molecular Formula: | C18H19NOS |
| SMILES: | CNCC[C@H](OC1=CC=CC2=CC=CC=C12)C1=CC=CS1 |
| Structure: |
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| DrugBank Description: | Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor. It was originally discovered in 1993 and developed by Eli Lilly and Company as LY248686. Duloxetine first received approval from the FDA in August, 2004 as Cymbalta for the treatment of Major Depressive Disorder. It has since received approval for a variety of indications including the treatment of neuropathic pain, Generalized Anxiety disorder, osteoarthritis, and stress incontinence. Duloxetine continues to be investigated for the treatment of pain in cancer, surgery, and more. |
| CAS Number: | 116539-59-4 |
| Molecular Weight: | 297.415 |
| DrugBank Indication: | **Indicated** for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. **Off-label** uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. |
| DrugBank Pharmacology: | Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. |
| DrugBank MoA: | Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, and α<sub>1</sub> adrenergic receptors. 5-HT<sub>2</sub> and α<sub>1</sub> are both G<sub>q</sub> coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP<sub>3</sub>/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT<sub>3</sub> functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub>, 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, α<sub>1</sub>-adrenergic, and α<sub>2</sub>-adrenergic receptors. 5-HT<sub>2</sub>, 5-HT<sub>3</sub>, and α<sub>1</sub>-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT<sub>1</sub> and α<sub>2</sub> receptors are G<sub>i</sub>/G<sub>o</sub> coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α<sub>1</sub> receptors predominates, vasoconstriction results as the G<sub>q</sub> coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. |
| Targets: | Sodium-dependent serotonin transporter inhibitor; Sodium-dependent noradrenaline transporter inhibitor; Sodium-dependent dopamine transporter inhibitor |
| Inclusion Criteria: | Therapeutic strategy associated |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs |
|---|
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I17 | 1596 | Mental depression | Mental depression | disease of mental health/ cognitive disorder/ mood disorder | Details |
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I15 | 1290 | Bone disease | A connective tissue disease that affects the structure or development of bone or causes an impairment of normal bone function. http://en.wikipedia.org/wiki/Bone_disease | disease of anatomical entity/ musculoskeletal system disease/connective tissue disease | Details |