From Self-sufficiency
Jump to: navigation, search
Systematic (IUPAC) name
(+)-(E)-1-[(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime
Legal status
Legal status
CAS Number 171655-91-7
ATC code none
PubChem CID 9614919
ChemSpider 7888898
Chemical data
Formula C16H20Cl2N2O
Molar mass 327.249 g/mol[[Script error: No such module "String".]]
Script error: No such module "collapsible list".
Script error: No such module "TemplatePar".Expression error: Unexpected < operator.

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.

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 much greater than humans, the amount of metabolites detected in their urine (and feces) was also much greater than for humans, who excrete more of the product intact. 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. Imine formation is a reversible process, and 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.


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.


BF is a TRI.

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=CHMe 1.53.4n.t0.370.0018
Me-O-N=CHMe,sulfate 1.33130.900.0030
Me-O-N=CHH,HCl 1.321.71.40.006
Me-O-CH2Me 21010nd0.015
Et-O-CH2Me 3.2811nd0.035

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.


Cite error: Invalid <references> tag; parameter "group" is allowed only.

Use <references />, or <references group="..." />

  1. Frackiewicz, EJ; Jhee; Shiovitz; Webster; Topham; Dockens; Whigan; Salazar; Cutler (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.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help); More than one of |author7= and |last7= specified (help); More than one of |author8= and |last8= specified (help); More than one of |author9= and |last9= specified (help) 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.  More than one of |author2= and |last2= specified (help) 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. 4.0 4.1 4.2 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.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help) edit
  5. Kozikowski, AP; Eddine Saiah, MK; Johnson, KM; Bergmann, JS (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