Identification
- Generic Name
- AV608
- DrugBank Accession Number
- DB05072
- Background
AV608 is a NK-1 antagonist. It is developed for the treatment of Social anxiety disorder (SAD), irritable bowel syndrome (IBS) and overactive bladder (OAB).
- Type
- Small Molecule
- Groups
- Investigational
- Synonyms
- Not Available
Pharmacology
- Indication
Investigated for use/treatment in anxiety disorders, irritable bowel syndrome (IBS), and urinary incontinence.
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Not Available
- Mechanism of action
An extensive body of scientific literature supports the potential therapeutic application of NK-1 antagonists to the treatment of anxiety disorders. At a biological level, there is a close anatomical association between Substance P, NK-1 receptors and monoamines. More specifically, ~50% of ascending serotonin neurons in the brain also co-express substance P, and norepinephrine cell bodies in the locus coeruleus express NK-1 receptors. In addition, it has been demonstrated that NK-1 receptor blockade can alter the firing pattern of both serotonin and norepinephrine neurons and increase hippocampal neurogenesis. At a functional level, NK-1 antagonists (including AV608) have broadly demonstrated activity in nearly all of the traditionally used preclinical assays to identify anxiolytic agents, including those assays that are predictive for both benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). Clinically, anxiety remains a high priority target for Industry, as evidenced by recent development activity in this area. It is known that the human intestinal mucosa expresses NK-1 receptors. These receptors are also found in the smooth muscle, arterioles, venules and cells associated with lymph nodules and co-localized with substance P, which is found throughout the gastrointestinal tract. Nerve fibers, including sensory fibers, come into close contact with mast cells, which also express NK-1 receptors. Furthermore, approximately 80% of visceral sensory afferents in the gut express substance P, and it is known that NK-1 receptors in the spinal cord mediate visceral hyperalgesia. Tachykinins are potent secretagogues at the small and large intestinal mucosa in several animal models as well as in the human colon, where there is a direct NK-1 receptor mediated response. Perhaps most important with respect to IBS is the observation that stimulation of sensory fibers or mast cells in the human intestinal tract causes the release of substance P and a consequent increase in epithelial ion transport through the activation of NK-1 receptors. The response to colorectal distension has often been used as a proxy for IBS. In this model, colorectal distension increases abdominal flinching, which is an indicator of pain. This procedure also activates a rectocolonic inhibitory reflex characterized by a decrease in colonic pressure and an increase in fluid transport. Several authors have now observed that NK-1 receptors mediate this rectocolonic inhibitory reflex. Decreased colonic pressure is related to increased colonic transit and these findings are therefore consistent with reports that stress increases intestinal transit, an effect blocked by NK-1 receptor antagonists. Overactive bladder is a common and distressing condition that has a profound effect on the daily living of affected individuals. This common cause of urinary incontinence describes a cluster of symptoms typified by urinary urgency, frequency, and urge urinary incontinence. Whereas the currently available anticholinergic drugs used to treat overactive bladder act on efferent nerves to counteract overactive bladder, essentially after it occurs, NK-1 antagonists appear to have promising therapeutic potential in their ability to affect the afferent nerves that modulate bladder contraction. A key potential advantage of NK-1 antagonists is that there may be essentially no decrement of detrusor contractility and no urinary retention risk, as is seen with current anticholinergic agents. This is because NK-1 antagonists inhibit sensory afferent nerves but not efferent nerves, which are important for normal and complete voiding of urine. Furthermore, NK-1 antagonists have a more favorable tolerability profile than observed with anticholinergic medications.
Target Actions Organism UNeurokinin 1 receptor Not Available Humans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Not Available
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- Not Available
- CAS number
- Not Available
- InChI Key
- Not Available
- InChI
- Not Available
- IUPAC Name
- Not Available
- SMILES
- Not Available
References
- General References
- Not Available
- External Links
- PubChem Substance
- 347909929
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 2 Completed Treatment Social Phobia 1 2 Terminated Treatment Overactive Bladder Syndrome (OABS) 1 1 Terminated Treatment Irritable Bowel Syndrome (IBS) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
- Not Available
- Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Tachykinin receptor activity
- Specific Function
- This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of aff...
- Gene Name
- TACR1
- Uniprot ID
- P25103
- Uniprot Name
- Substance-P receptor
- Molecular Weight
- 46250.5 Da
Drug created at October 21, 2007 22:23 / Updated at June 12, 2020 16:52