Lofentanil is a powerful synthetic opioid with a very high affinity for mu-opioid receptors. While its properties make it unsuitable for most clinical applications due to its long duration of action, it has become a valuable tool in scientific research, particularly for studying opioid receptors and their role in pain perception and analgesia [].

• Understanding Opioid Binding: Lofentanil’s high affinity for mu-opioid receptors allows researchers to use it to label and visualize these receptors in cell cultures and brain tissue sections. This helps scientists understand the distribution and function of these receptors in the nervous system [].
• Studying Receptor Signaling Pathways: By observing the cellular responses triggered by Lofentanil binding to mu-opioid receptors, researchers can investigate the downstream signaling pathways involved in pain perception and analgesia. This knowledge can aid in the development of new pain medications with fewer side effects [].
• Opioid Receptor Subtype Differentiation: Lofentanil exhibits selectivity towards certain subtypes of mu-opioid receptors compared to other opioids. This property allows researchers to differentiate between these subtypes and understand their specific roles in pain signaling [].

Lofentanil, also known as lofentanyl, is a synthetic opioid analgesic that is recognized as one of the most potent analgesics available. It is an analogue of fentanyl, originally developed in the 1960s, and is chemically classified as 3-methyl-4-carbomethoxyfentanyl. Lofentanil exhibits a high affinity for the μ-opioid receptor, which is responsible for its analgesic effects. It is structurally similar to carfentanil, another potent opioid, but with notable differences in potency and duration of action. The molecular formula of lofentanil is C25H32N2O3, with a molar mass of approximately 408.54 g/mol  .

Typical of opioid compounds. These include:

• Hydrolysis: Lofentanil may hydrolyze under acidic or basic conditions, potentially affecting its potency and stability.
• Reduction: The compound can be reduced to yield other derivatives that may exhibit different pharmacological properties.
• Alkylation: Alkylation reactions may modify the piperidine ring structure, altering its binding affinity to opioid receptors.

These reactions are essential for understanding the compound’s stability and potential transformation during synthesis or metabolism.

Lofentanil is primarily known for its potent analgesic properties, acting mainly as a full agonist at the μ-opioid receptor. Its biological activity includes:

• Analgesia: It provides significant pain relief, making it a subject of research for pain management.
• Respiratory Depression: Like other opioids, lofentanil can cause respiratory depression, which poses risks in clinical settings.
• Tolerance Development: Rapid tolerance can develop due to its high binding affinity, leading to increased dosages for the same effect over time  .

The synthesis of lofentanil typically involves several steps:

• Starting Material: The synthesis often begins with piperidine derivatives.
• Substitution Reactions: Key steps include introducing the carbomethoxy group at the 4-position and methylation at the 3-position of the piperidine ring.
• Purification: The final product is purified through crystallization or chromatography to ensure high purity suitable for research applications.

Various synthetic pathways have been explored in literature to optimize yields and reduce by-products  .

Lofentanil’s primary applications are in research rather than clinical use due to its potency and associated risks. Its applications include:

• Research on Opioid Receptors: Lofentanil is used in studies investigating μ-opioid receptor interactions and mechanisms.
• Potential Analgesic Development: Although not widely used clinically, it serves as a model compound for developing new analgesics with improved safety profiles.

Due to its potency and long duration of action, it is not suitable for routine medical applications like surgical anesthesia  .

Studies have indicated that lofentanil interacts significantly with both μ-opioid and κ-opioid receptors. Key findings include:

• Receptor Binding Affinity: Lofentanil displays high binding affinity for μ-opioid receptors (K_i = 8.2 nM) and acts as a full agonist (EC_50 = 153 nM) .
• Side Effects Profile: Its side effects mirror those of other potent opioids, including nausea and respiratory depression. The long duration of action raises concerns about prolonged effects and overdose potential  .

Lofentanil shares structural similarities with several other potent opioids. Here are some comparable compounds:

Lofentanil’s unique characteristics lie in its combination of high potency and longer duration compared to other fentanyl analogues like sufentanil or remifentanil. This makes it particularly interesting for research into opioid receptor dynamics but limits its practical applications due to safety concerns  .

Molecular Formula and Composition

Lofentanil possesses the molecular formula C₂₅H₃₂N₂O₃, representing a complex organic compound with a molecular weight of 408.542 grams per mole [2] [3]. The compound contains twenty-five carbon atoms, thirty-two hydrogen atoms, two nitrogen atoms, and three oxygen atoms, forming a sophisticated molecular architecture that distinguishes it from simpler opioid structures [1] [2]. The exact mass of lofentanil is 408.241293 atomic mass units, with a monoisotopic mass of 408.241292898 [3] [7]. This molecular composition places lofentanil among the more structurally complex fentanyl analogues, incorporating multiple functional groups that contribute to its distinctive chemical properties [2] [21].

The elemental composition reveals a carbon-to-nitrogen ratio of 12.5:1 and a molecular framework that accommodates significant structural diversity through its multiple aromatic and aliphatic components [2] [3]. The presence of three oxygen atoms distributed across different functional groups creates multiple sites for potential chemical interactions and contributes to the compound’s overall polarity characteristics [8].

Stereochemistry and Isomeric Configurations

Lofentanil exhibits complex stereochemical properties due to the presence of two chiral centers located at the 3- and 4-positions of the piperidine ring [12] [6]. This configuration generates four possible stereoisomers: (3R,4S), (3S,4R), (3S,4S), and (3R,4R) [12]. The original lofentanil compound is characterized by the (3R,4S) configuration, also known as the cis-(-) isomer, which represents the most pharmacologically active form [12] [21].

The stereochemical distinctions between these isomers are critical for understanding the compound’s properties [6] [12]. The two cis isomers, (3R,4S) and (3S,4R), demonstrate significantly different binding characteristics, with the (3R,4S) isomer showing substantially higher binding affinity at the μ-opioid receptor compared to the (3S,4R) configuration [12]. The trans isomers, (3S,4S) and (3R,4R), exhibit intermediate activity profiles and demonstrate less impact from the 3-methyl modification when positioned at the equatorial position of the piperidine ring [12].

Computational studies have revealed that the additional methyl group at the 3-position of the piperidine ring in (3S,4R)-lofentanil creates an energy barrier difference of approximately 6 kilocalories per mole compared to its corresponding states, while (3R,4S)-lofentanil shows a reversed energetic trend [12]. The conformational analysis indicates that these stereoisomers maintain similar free energy surfaces to carfentanil, particularly the trans isomers [6] [12].

International Union of Pure and Applied Chemistry Nomenclature and Chemical Identifiers

The systematic International Union of Pure and Applied Chemistry name for lofentanil is methyl (3S,4R)-3-methyl-1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate [2] [4]. Alternative nomenclature includes methyl 3-methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate and 4-piperidinecarboxylic acid, 3-methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-, methyl ester [3] [2].

The compound is registered under Chemical Abstracts Service registry number 61380-40-3 [1] [2] [7]. The Unique Ingredient Identifier code assigned by the United States Food and Drug Administration is 7H7YQ564XV [2] [7]. Additional chemical database identifiers include PubChem Compound Identification Number 65499 [2], ChemSpider Identification Number 110226 [3], and DrugBank Identification Number DB09174 [7].

The International Chemical Identifier string for lofentanil is InChI=1S/C25H32N2O3/c1-4-23(28)27(22-13-9-6-10-14-22)25(24(29)30-3)16-18-26(19-20(25)2)17-15-21-11-7-5-8-12-21/h5-14,20H,4,15-19H2,1-3H3/t20-,25+/m0/s1 [2] [4]. The corresponding International Chemical Identifier Key is IMYHGORQCPYVBZ-NBGIEHNGSA-N [2] [4]. The Simplified Molecular Input Line Entry System representation is CCC(=O)N(C1=CC=CC=C1)[C@@]2(CCN(C[C@@H]2C)CCC3=CC=CC=C3)C(=O)OC [2] [4].

Physical Constants and Molecular Parameters

Lofentanil exists as a white solid at room temperature with a density of 1.118 grams per cubic centimeter [8]. The compound exhibits a calculated boiling point of 514.377 degrees Celsius at 760 millimeters of mercury pressure [8]. The flash point is determined to be 264.886 degrees Celsius [8]. Melting point data for the free base form of lofentanil is not readily available in the literature [8].

The logarithm of the partition coefficient (LogP) value for lofentanil is 3.86380, indicating significant lipophilic characteristics [8]. The compound demonstrates an index of refraction of 1.566 [8]. The polar surface area is calculated to be 49.85000 square angstroms [8], which falls within the range typically associated with compounds capable of crossing biological membranes.

The molecular parameters reveal that lofentanil possesses moderate to high lipophilicity compared to other fentanyl analogues [8]. This lipophilic nature contributes to the compound’s extended duration of action and tissue distribution characteristics [21]. The physical constants suggest that lofentanil would remain stable under normal atmospheric conditions but would require elevated temperatures for phase transitions [8].

Structural Features and Functional Groups

Lofentanil incorporates multiple distinct functional groups that define its chemical behavior and molecular interactions [2] [7]. The central piperidine ring system serves as the core scaffold, providing the basic nitrogen functionality essential for receptor binding [2] [12]. This six-membered saturated heterocycle contains two chiral centers that generate the compound’s stereochemical complexity [12].

The 4-position of the piperidine ring bears a methyl ester group (-COOMe), representing the carbomethoxy modification that significantly enhances binding potency compared to unsubstituted analogues [2] [21]. This ester functionality is characteristic of the carfentanil family of compounds and contributes to the compound’s increased receptor affinity [6] [12]. Adjacent to the ester group, a propionamide substituent (-CO-CH₂-CH₃) extends from the nitrogen at the 4-position, forming part of the tertiary amide system crucial for receptor recognition [2] [16].

The phenethyl chain (-CH₂-CH₂-Ph) attached to the 1-position nitrogen provides the N-terminal aromatic system that participates in receptor binding through aromatic stacking interactions [2] [12]. This phenethyl moiety is conserved across most fentanyl analogues and represents a critical structural element for maintaining biological activity [24].

The aniline component (C₆H₅-NH-) forms part of the propionamide group and contributes additional aromatic character to the molecule [2] [3]. This aromatic system enhances the compound’s ability to engage in π-π interactions with receptor binding sites [12]. The 3-position of the piperidine ring contains a methyl substituent (-CH₃) that distinguishes lofentanil from carfentanil and introduces additional steric constraints that influence the compound’s conformational preferences [6] [12].