Bicifadine
Encyclopedia
Bicifadine is a serotonin-norepinephrine reuptake inhibitor
(SNRI) developed by DOV Pharmaceutical
. It has been developed as an analgesic
and is currently under development for the treatment of various pain
conditions. Phase III trials
were completed in 2006 for treating chronic low back pain
, and the drug is currently being tested to assess its efficacy in treating pain associated with osteoarthritis
, acute post-surgical pain, neuropathic pain
and pain associated with dental surgery.http://www.dovpharm.com/sub_page/products_body.html Its usefulness in surgical or dental pain is dubious, however, as most monoamine uptake-inhibiting antidepressants have little if any effect in treating acute pain—they are only effective in cases of chronic neuropathic pain (much like their antidepressant properties, the analgesic properties of monoamine uptake inhibitors are not fully manifested until 1–2 weeks of continuous treatment).
Bicifadine represents a novel class of drug using a non-opioid
, non-NSAID mechanism for the treatment of pain, which should have less abuse potential than opioid drugs and less propensity to cause gastric ulcers than NSAID drugs. While the drug is purported to be a serotonin (SERT) and noradrenaline transporter (NET) inhibitor, it also has effects at the dopamine transporter (DAT), effectively making it a broad-spectrum monoamine transporter inhibitor or "triple reuptake inhibitor." While its efficacy at the DAT is lower than its efficacy at either the SERT or the NET, it is still capable of increasing the perisynaptic concentration of all three monoamines. Bicifadine is not the first antidepressant drug used in the treatment of pain, as the older tricyclic antidepressants (e.g. desipramine
and amitriptyline
) and the newer SNRI drug duloxetine
have previously been approved for the treatment of neuropathic pain and disorders like fibromyalgia
. Moreover, some weak or atypical opioid drugs such as tramadol
and the newer agent tapentadol
also function as noradrenaline reuptake inhibitors, a property that contributes to their overall therapeutic effect.
Preliminary results suggest that bicifadine has an analgesic efficacy slightly stronger than codeine
and approximately equivalent to tramadol, although side effects such as nausea
and headache
were more common with bicifadine than with tramadol.http://www.joacp.org/index.php?option=com_content&task=view&id=48&Itemid=58
has been published which begins with a benzyl cyanide
derivative and a halohydrin
. The final step in the synthesis is shown below, where thionyl chloride
is used to close the pyrrolidine
ring.
DOV scientists and their collaborators have developed several routes to 1-ARYL-3-AZABICYCLO[3.1.0] HEXANES.
The above scheme is exemplary.
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
(SNRI) developed by DOV Pharmaceutical
DOV Pharmaceutical
DOV Pharmaceutical, a biotechnology company, focuses on therapies primarily for central nervous system conditions. The firm's lead drug candidate, Indiplon, is said to treat insomnia. Indiplon targets the same subset of neurotransmitter receptors affected by Valium and Xanax, but with more...
. It has been developed as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and is currently under development for the treatment of various pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
conditions. Phase III trials
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
were completed in 2006 for treating chronic low back pain
Low back pain
Low back pain or lumbago is a common musculoskeletal disorder affecting 80% of people at some point in their lives. In the United States it is the most common cause of job-related disability, a leading contributor to missed work, and the second most common neurological ailment — only headache is...
, and the drug is currently being tested to assess its efficacy in treating pain associated with osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
, acute post-surgical pain, neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
and pain associated with dental surgery.http://www.dovpharm.com/sub_page/products_body.html Its usefulness in surgical or dental pain is dubious, however, as most monoamine uptake-inhibiting antidepressants have little if any effect in treating acute pain—they are only effective in cases of chronic neuropathic pain (much like their antidepressant properties, the analgesic properties of monoamine uptake inhibitors are not fully manifested until 1–2 weeks of continuous treatment).
Bicifadine represents a novel class of drug using a non-opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
, non-NSAID mechanism for the treatment of pain, which should have less abuse potential than opioid drugs and less propensity to cause gastric ulcers than NSAID drugs. While the drug is purported to be a serotonin (SERT) and noradrenaline transporter (NET) inhibitor, it also has effects at the dopamine transporter (DAT), effectively making it a broad-spectrum monoamine transporter inhibitor or "triple reuptake inhibitor." While its efficacy at the DAT is lower than its efficacy at either the SERT or the NET, it is still capable of increasing the perisynaptic concentration of all three monoamines. Bicifadine is not the first antidepressant drug used in the treatment of pain, as the older tricyclic antidepressants (e.g. desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
and amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
) and the newer SNRI drug duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
have previously been approved for the treatment of neuropathic pain and disorders like fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
. Moreover, some weak or atypical opioid drugs such as tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
and the newer agent tapentadol
Tapentadol
Tapentadol is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. While its analgesic actions have been compared to tramadol and oxycodone, its general potency is somewhere between tramadol and morphine in...
also function as noradrenaline reuptake inhibitors, a property that contributes to their overall therapeutic effect.
Preliminary results suggest that bicifadine has an analgesic efficacy slightly stronger than codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
and approximately equivalent to tramadol, although side effects such as nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
were more common with bicifadine than with tramadol.http://www.joacp.org/index.php?option=com_content&task=view&id=48&Itemid=58
Total synthesis
A total synthesisTotal synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
has been published which begins with a benzyl cyanide
Benzyl cyanide
Benzyl cyanide is an organic compound with the chemical formula C6H5CH2CN. This colorless oily aromatic liquid is a precursor to several derivatives.-Synthesis, reactions, and applications:...
derivative and a halohydrin
Halohydrin
A halohydrin or a haloalcohol is a type of organic compound or functional group in which one carbon atom has a halogen substituent, and an adjacent carbon atom has a hydroxyl substituent. They are derived from alcohols are therefore characterized by the presence of both the hydroxyl functional...
. The final step in the synthesis is shown below, where thionyl chloride
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
is used to close the pyrrolidine
Pyrrolidine
Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
ring.
DOV scientists and their collaborators have developed several routes to 1-ARYL-3-AZABICYCLO[3.1.0] HEXANES.
The above scheme is exemplary.