Brasofensine (NS-2214, BMS-204756) is a

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...

that had been under

development Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking, development phase, including finance and budgeting *Development (music), the process thematic material is reshaped * Photograph ...

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

for the treatment of

Parkinson's Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

and Alzheimer's diseases. In

animal models of Parkinson's disease Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra ...

, brasofensine was effective in stimulating LMA and reversing

akinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...

. Phase II trials in humans were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg; however, development was stopped after ''in vivo'' cis-anti isomerization of the 2α-methyloxime group was reported. The isomerization of brasofensine did not involve

epimerization In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...

at 2-position of the tropane ring, but rather involved the ''E''/''Z''-isomerization of the

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

(i.e. "methyl-aldoxime"). It was believed that this process occurs ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'', although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion. The (''Z'')-isomer has been assigned the name BMS-205912. In Parkison's disease, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra brain region.

Metabolism and distribution

Brasofensine is not particularly stable and is readily metabolized. It was studied in humans in doses ranging from 2-50 mg. Because metabolism in rats is much greater than in 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. In

radiolabeling A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by ...

studies using ¹⁴C, most (~90%) of the ¹⁴C was detected in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

of humans, whereas for rats as much as 80% of the ¹⁴C was in their feces. It is well known that a

Schiff base In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...

is more stable than a regular imine. Imine formation is a reversible process, and in the study by Zhu ''et al''., none of the aldehyde was recovered/detected by GC-MS. Instead, the breakdown products were ''N''-demethyl metabolites.

References

{{Monoamine reuptake inhibitors Serotonin–norepinephrine–dopamine reuptake inhibitors Stimulants Sympathomimetic amines Tropanes Aldoximes Abandoned drugs