4 Fluorococaine

Description

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4’-Fluorococaine is a synthetic cocaine analog featuring a fluorine atom at the 4′ position of the benzoyl moiety. Structurally, it retains the tropane backbone of cocaine but replaces the hydrogen at the 4′ aromatic position with fluorine (C₁₇H₂₀FNO₄) . This modification alters its pharmacological profile, making it a valuable tool for neuroimaging and receptor-binding studies.

Originally synthesized for positron emission tomography (PET) research, this compound (labeled with ¹¹C or ¹⁸F) was used to investigate cocaine metabolism and transporter binding in primate brains . In vitro assays demonstrated its equipotency to cocaine at dopamine transporters (DAT) but a 100-fold greater potency at serotonin transporters (SERT) . These properties, combined with its metabolic stability compared to cocaine, have made it a key compound for studying monoamine reuptake mechanisms and addiction pathways.

Preparation Methods
The synthesis of 4’-Fluorococaine involves several steps, starting with the preparation of the tropane skeleton. The key steps include:

Formation of the tropane ring: This is typically achieved through a series of cyclization reactions.

Introduction of the fluorobenzoyloxy group: This step involves the esterification of the tropane skeleton with 4-fluorobenzoic acid under acidic conditions.

Methylation: The final step involves the methylation of the carboxylate group to form the methyl ester.

Chemical Reactions Analysis
Metabolic Hydrolysis Reactions
4’-Fluorococaine undergoes rapid ester hydrolysis in vivo, similar to cocaine, producing metabolites through cleavage of its methyl ester and benzoyl ester groups1.

Primary Metabolic Pathways of 4’-Fluorococaine :

Reaction Enzymes Involved Major Metabolites
Methyl ester hydrolysis Hepatic esterases 4’-Fluorobenzoylecgonine
Benzoyl ester hydrolysis Plasma esterases 4’-Fluoroecgonine methyl ester
Kinetic Data:

Half-life : Shorter than cocaine due to enhanced esterase susceptibility1.

Bioactivity : Metabolites lack significant dopamine reuptake inhibition but retain partial serotonergic activity2.

Comparative Reactivity of 4’-Fluorococaine with Cocaine

4’-Fluorococaine’s fluorinated structure alters its electronic and steric properties, impacting reactivity:

Property Cocaine 4’-Fluorococaine

Electrophilicity Moderate Increased (due to -F electron withdrawal)
Metabolic Stability Low (rapid hydrolysis) Lower (faster ester cleavage)1
Oxidative Susceptibility Prone to N-oxidation Enhanced resistance to oxidation
Mechanistic Insights:

The electron-withdrawing fluorine group reduces electron density at the benzoyloxy moiety, accelerating hydrolysis but stabilizing against oxidative degradation21.

Radical Reactions (Theoretical)
While not experimentally documented for 4’-Fluorococaine, analogous fluorinated tropanes participate in radical-mediated reactions under UV light or with initiators like peroxides. Potential pathways include:

C-F Bond Homolysis : Generating fluorinated radicals for coupling reactions3.

H-Abstraction : Leading to defluorination or cross-linking4.

Scientific Research Applications
Chemistry
4′-Fluorococaine serves as a reference compound in studies of tropane derivatives, aiding in understanding their chemical properties and interactions.

Biology
Researchers utilize this compound to explore its effects on serotonin reuptake inhibition across various biological systems. Its unique profile allows for comparative studies with other psychoactive substances.

Medicine
The compound is investigated as a model for developing new therapeutic agents targeting serotonin reuptake. Its strong serotonin reuptake inhibition suggests potential applications in treating mood disorders or conditions related to serotonin dysregulation .

Industry
While not widely used industrially, this compound provides insights into the synthesis and properties of fluorinated organic compounds. Its study contributes to advancements in organic chemistry and drug development .

Case Studies and Research Findings
Several studies have documented the effects and potential applications of this compound:

Pharmacological Profile Study: Research indicates that this compound exhibits significantly altered pharmacological effects in animal models compared to cocaine, highlighting its stronger impact on serotonin pathways .
Therapeutic Potential: Investigations into its use as a therapeutic agent for mood disorders have shown promise due to its selective serotonin reuptake inhibition .
Chemical Reactivity Studies: Studies focusing on the chemical reactivity of this compound have provided insights into its behavior under various conditions, informing future synthetic applications .
Mechanism of Action
4’-Fluorococaine exerts its effects primarily through the inhibition of serotonin reuptake. It binds to the serotonin transporter, preventing the reabsorption of serotonin into presynaptic neurons. This leads to an increase in serotonin levels in the synaptic cleft, enhancing serotonergic neurotransmission. Additionally, it has moderate inhibitory effects on dopamine reuptake, contributing to its stimulant properties .

Comparison with Similar Compounds
Cocaine
Pharmacological Profile :

Property Cocaine 4′-Fluorococaine
DAT Affinity (IC₅₀) ~200 nM ~200 nM
SERT Affinity (IC₅₀) ~2000 nM ~20 nM
NET Affinity (IC₅₀) ~500 nM ~500 nM
Metabolic Stability Low (rapid hydrolysis) High (resists esterase cleavage)
Cocaine’s rapid hydrolysis by esterases limits its utility in PET imaging, whereas this compound’s fluorine substitution enhances stability, enabling clearer visualization of transporter binding .

PET Imaging :
In baboon studies, 4′-[¹⁸F]fluorococaine and [¹¹C]cocaine showed nearly identical brain uptake kinetics despite this compound’s higher SERT affinity. This suggests that DAT binding dominates in vivo, masking SERT contributions in regions like the striatum .

4-Fluorotropacocaine
Structural Differences :
4-Fluorotropacocaine (CAS 172883-97-5) replaces the methyl ester of cocaine with a 4-fluorobenzoyl group on the tropane nitrogen. Unlike this compound, it lacks the benzoyl ester linkage, altering transporter interactions .
Pharmacology: While 4-fluorotropacocaine is used as an analytical standard, its DAT/SERT selectivity remains less characterized. Limited studies suggest weaker DAT binding than cocaine, making it less relevant for neuroimaging .
Phenyltropane Derivatives (CFT, Altropane)
CFT (WIN 35,428) :
CFT, a phenyltropane analog, exhibits higher DAT selectivity than cocaine. Unlike this compound, it shows minimal SERT/NET activity, making it a pure DAT tracer in PET studies .
Altropane (IACFT) :
Altropane’s iodine substitution enhances DAT affinity (IC₅₀ ~5 nM) and metabolic stability. Compared to this compound, it is more suitable for quantifying DAT density in neurodegenerative diseases .
Dichloropane and Dimethocaine
Dichloropane :
A chlorinated cocaine analog, dichloropane has higher DAT affinity than cocaine but lacks this compound’s SERT potency. It was among the first research chemicals marketed as a cocaine substitute but faced regulatory restrictions .
Dimethocaine :
Dimethocaine’s esterified structure reduces CNS penetration and potency. Unlike this compound, it primarily acts as a local anesthetic with negligible transporter activity .
Research Findings and Implications
Serotonin Transporter Selectivity: this compound’s 100-fold SERT potency over cocaine (IC₅₀ ~20 nM vs. However, in vivo PET data suggest that DAT binding overshadows SERT effects in striatal regions, complicating interpretation .
Regulatory Status : Classified as a controlled substance in Canada (CDSA Schedule I) due to its ecgonine derivative status, this compound remains unlisted in U.S. schedules but may fall under analog laws .