3-Methylthiofentanyl
[CAS# 86052-04-2]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Piperidines
• Name: 3-Methylthiofentanyl
• Synonyms: N-[3-methyl-1-(2-thiophen-2-ylethyl)piperidin-4-yl]-N-phenylpropanamide
• Molecular Formula: C₂₁H₂₈N₂OS
• Molecular Weight: 356.52
• CAS Registry Number: 86052-04-2
• SMILES: CCC(=O)N(C1CCN(CC1C)CCC2=CC=CS2)C3=CC=CC=C3

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 474.0±40.0 ºC 760 mmHg (Calc.)^*
• Flash point: 240.4±27.3 ºC (Calc.)^*
• Index of refraction: 1.584 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Controlled Substance: DEA Drug Code Number: 9833

Discovory and Applicatios

3-Methylthiofentanyl is a synthetic analog of fentanyl, belonging to the broader class of fentanyl-related substances known for their high potency as μ-opioid receptor agonists. These analogs are structurally derived from fentanyl by modification of the N-aryl or N-alkyl substituents, which significantly influences their pharmacological activity and receptor binding affinity. In the case of 3-methylthiofentanyl, a methyl group is introduced at the 3-position of the phenethyl side chain, which alters the compound’s physicochemical and pharmacodynamic profile.

This analog was initially synthesized during structure-activity relationship (SAR) studies exploring the opioid receptor affinity of various fentanyl derivatives. The introduction of substituents at different positions on the phenethyl moiety was aimed at assessing the tolerance and flexibility of the opioid receptor binding site. It was found that small alkyl substituents, such as methyl groups at specific positions, can either retain or enhance receptor affinity, depending on their orientation and electronic effects.

3-Methylthiofentanyl has no known medical use and has not been developed or approved for clinical application. Instead, it has emerged primarily in the context of illicit drug markets, especially during the proliferation of non-pharmaceutical fentanyl analogs. These substances have been manufactured clandestinely and sold as substitutes for or adulterants in heroin and other opioids, often without clear labeling, posing severe risks of unintentional overdose due to their high potency and variable pharmacokinetics.

Pharmacologically, 3-methylthiofentanyl acts as a potent μ-opioid receptor agonist, similar to fentanyl. It induces analgesia, euphoria, sedation, and respiratory depression through its action on central nervous system opioid receptors. Due to its structural similarity to fentanyl, it is presumed to have a similar onset and duration of action, although exact pharmacokinetic data are limited. The addition of a methyl group may affect the lipophilicity of the molecule, potentially influencing its ability to cross the blood-brain barrier and thus its potency and onset profile.

The synthesis and identification of 3-methylthiofentanyl have been documented in forensic and toxicological literature, especially in the analysis of overdose cases involving unknown synthetic opioids. Analytical detection typically relies on advanced techniques such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS), which enable specific identification even in complex biological matrices.

Due to its high potency and the narrow margin between therapeutic and lethal doses, 3-methylthiofentanyl has been associated with significant morbidity and mortality. Its use outside of controlled research environments carries considerable risk, particularly when users are unaware of the exact compound and its strength. Accidental overdoses often occur due to the potent respiratory depressant effects of the compound, which may not be adequately reversed by standard doses of opioid antagonists such as naloxone, requiring repeated or higher-dose administration.

In response to its appearance in illicit drug markets, regulatory agencies in several jurisdictions have classified 3-methylthiofentanyl as a controlled substance or placed it under temporary emergency scheduling. These measures are intended to curb its distribution and mitigate its public health impact, particularly in light of the ongoing opioid crisis.

3-Methylthiofentanyl exemplifies the broader challenge posed by novel synthetic opioids, where slight chemical modifications yield compounds with high pharmacological activity but minimal safety data. The emergence of such analogs has prompted intensified surveillance, analytical method development, and legislative responses aimed at limiting their spread and addressing the evolving landscape of synthetic opioid misuse.

References

21 CFR � 1308.11 - Schedule I. Code of Federal Regulations, Title 21.
URL: https://www.ecfr.gov/current/title-21/chapter-II/part-1308/section-1308.11