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Brasofensine
Systematic (IUPAC) name
(+)-(E)-1-[(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime
Identifiers
CAS number 171655-91-7
ATC code none
PubChem 9614919
ChemSpider 7888898
Chemical data
Formula C16H20Cl2N2O 
Mol. mass 327.249 g/mol
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat.  ?
Legal status  ? (UK)
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Brasofensine (NS-2214, BMS-204756) is a phenyltropane that had been under development for the treatment of Parkinson's and Alzheimer's disease. Phase II trials were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg,[1] however development was stopped after in vivo cis-anti isomerization of the 2α-methyloxime group was reported.[2] In animal models of Parkinson's disease, brasofensine was effective in stimulating LMA and reversing akinesia.[3]

The isomerization of brasofensine is not between the alpha and beta positions on the 2 position of the tropane ring but rather the E/Z isomerization of the imine (i.e. "methyl-aldoxime").[4]

The (Z)-isomer has been consigned the name BMS-205912

The inversion barrier for a methylaldoxime is not anticipated to be particularly high.

In PD, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra brain region. Subsequently there is decreased dopaminergic neurotransmission, resulting in movement disorders, slurred speech, and the like. The object of a DRI is to "make the best out of" the dopamine that is still available. Additionally, a DRI can be expected to enhance the effectiveness of exogenously delivered dopamine, in the form of L-DOPA.

Contents

Metabolism and Distribution

NS-2214 is not particularly stable and is readily metabolized. 50 mg was the dosage that was tried on humans, although the starting dose was 2 mg.[4] Interestingly, because rats metabolism is that much greater than humans, the amount of metabolites detected in their urine (and feces) was much greater than for humans who excreted a greater amount of the product intact.

Interestingly, for humans most (~90%) of the 14C was detected in the urine, whereas for rats as much as 80% of the 14C was in their feces.

It is well-known that a Schiff base is more stable than a regular imine.

Obviously, imine formation is a reversible process. In the study by Zhu et al.,[4] none of the aldehyde was recovered/detected by GC-MS.

Instead, the break down products were N-demethyl metabolites.

See also: fluvoxamine.

Chemistry

The ester was first reduced to the alcohol, then oxidized to the aldehyde, followed by condensation with methoxyamine. Methods have been reported for the direct reduction of esters to aldehydes, however in practice there has been some difficulty in effecting this transformation.[5] 17-20

In particular, the fragility of the aldehyde meant that it collapsed to the alcohol and was not isolable even though a wide assortment of reducing agents and reactions conditions were attempted.

Following this, Swern oxidation was employed to obtain the corresponding aldehyde.

Patents

BF is a TRI.
BTfensine.GIF

2-Position N NT IC50 (nM) DT IC50 (nM) ST IC50 (nM) In vivo ED50 (mg/kg) In vitro IC50 (μM)
Syn Me-O-N=CH Me 1.5 3.4 n.t 0.37 0.0018
Me-O-N=CH Me,sulfate 1.3 3 13 0.90 0.0030
Me-O-N=CH H,HCl 1.3 2 1.7 1.4 0.006
Me-O-CH2 Me 2 10 10 nd 0.015
Et-O-CH2 Me 3.2 8 11 nd 0.035
Ph-S-CH2 Me 2.8 4.3 9.2 nd nd

The following rating scale is used for the high intensity stereotypy on the condition that the behavioural syndromes are as described above:

+=only stereotyped sniffing ++=stereotyped sniffing and episodic licking +++=continuous licking and/or biting gnawing Compound (1R,2R,3S)-3-(p,m-Dichlorophenyl)tropane-O-methyl-aldoxime Dose(p.o.) Activity 15 mg/kg +++ is the lowest dosis giving the activity indicated.

References

  1. ^ Frackiewicz, EJ; Jhee; Shiovitz; Webster; Topham; Dockens; Whigan; Salazar et al. (2002). "Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa". The Annals of pharmacotherapy 36 (2): 225–30. doi:10.1345/aph.1A152. PMID 11847938.  edit
  2. ^ Runyon, SP; Carroll (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Current topics in medicinal chemistry 6 (17): 1825–43. doi:10.2174/156802606778249775. ISSN 1568-0266. PMID 17017960.  edit
  3. ^ Pearce, R.; Smith, L.; Jackson, M.; Banerji, T.; Scheel-Krüger, J.; Jenner, P. (2002). "The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets". Movement disorders : official journal of the Movement Disorder Society 17 (5): 877–886. doi:10.1002/mds.10238. PMID 12360536.  edit
  4. ^ a b c Zhu, M.; Whigan, D.; Chang, S.; Dockens, R. (2008). "Disposition and metabolism of 14Cbrasofensine in rats, monkeys, and humans". Drug metabolism and disposition: the biological fate of chemicals 36 (1): 24–35. doi:10.1124/dmd.107.016139. PMID 17908924.  edit
  5. ^ Kozikowski, AP; Eddine Saiah; Johnson; Bergmann (1995). "Chemistry and biology of the 2 beta-alkyl-3 beta-phenyl analogues of cocaine: subnanomolar affinity ligands that suggest a new pharmacophore model at the C-2 position". Journal of medicinal chemistry 38 (16): 3086–93. doi:10.1021/jm00016a012. PMID 7636872.  edit







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