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Bicifadine
Systematic (IUPAC) name
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane
Identifiers
CAS number 71195-57-8
ATC code none
PubChem 47953
Chemical data
Formula C 12H15N 
Mol. mass 173.25 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life 1.6 hours
Excretion renal
Therapeutic considerations
Pregnancy cat.  ?
Legal status  ? (US)
Routes oral

Bicifadine (DOV-220,075) is a serotonin-norepinephrine reuptake inhibitor (SNRI) developed by DOV Pharmaceutical.[1] It has been developed as an analgesic and is currently under development for the treatment of various pain conditions.[2] 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.[1] 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.[3] 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."[4] 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.[2]

Synthesis

A total synthesis 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[1].

BicifadineSynthesisXu2007.svg

See also

References

  1. ^ a b Xu F, Murry JA, Simmons B, Corley E, Fitch K, Karady S, Tschaen D. Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947. Organic Letters. 2006 Aug 17;8(17):3885-8.
  2. ^ Krieter PA, Gohdes M, Musick TJ, Duncanson FP, Bridson WE. Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans. Drug Metabolism and Disposition. 2007 Nov 8.
  3. ^ Wang RI, Johnson RP, Lee JC, Waite EM. The oral analgesic efficacy of bicifadine hydrochloride in postoperative pain. Journal of Clinical Pharmacology. 1982 Apr;22(4):160-4.
  4. ^ Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, Krieter PA, Lippa AS, Skolnick P, Koustova E. Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1208-25.







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