2-(Dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride

2-(Dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride, commonly known as tramadol hydrochloride, is a synthetic opioid analgesic used to treat moderate to severe pain. This compound operates through multiple mechanisms, primarily affecting the central nervous system (CNS). This article explores its biological activity, including pharmacodynamics, pharmacokinetics, and potential side effects.

Chemical Structure and Properties

• IUPAC Name : this compound
• Molecular Formula : C16H26ClNO2
• Molecular Weight : 299.84 g/mol

Tramadol exerts its analgesic effects through:

• Opioid Receptor Agonism : It binds to μ-opioid receptors in the brain, inhibiting pain transmission.
• Monoamine Reuptake Inhibition : Tramadol inhibits the reuptake of norepinephrine and serotonin, enhancing descending pain modulation pathways .

Pharmacokinetics

• Absorption : Rapidly absorbed after oral administration; peak plasma concentrations occur within 1-2 hours.
• Metabolism : Primarily metabolized in the liver via cytochrome P450 enzymes (CYP2D6 and CYP3A4), producing active metabolites such as O-desmethyltramadol .
• Elimination : The elimination half-life ranges from 5 to 7 hours, with renal excretion of metabolites being the primary route of elimination.

Analgesic Effects

Tramadol is effective for various types of pain, including:

• Postoperative Pain : Demonstrated significant efficacy in managing pain following surgical procedures .
• Chronic Pain Conditions : Used in conditions such as osteoarthritis and neuropathic pain.

Comparative Efficacy

Tramadol has been compared with traditional opioids:

Case Studies

• Postoperative Pain Management : A study involving patients post knee surgery found tramadol to be effective in reducing pain scores compared to placebo .
• Chronic Pain Management : In a cohort of patients with fibromyalgia, tramadol significantly improved pain levels and quality of life compared to baseline measurements .

Side Effects and Safety Profile

While tramadol is generally well-tolerated, it can cause side effects such as:

• Nausea
• Dizziness
• Constipation
• Risk of seizures, particularly at higher doses or in combination with certain medications .

Basic Research Questions

Q. What are the recommended storage conditions for 2-(Dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride to ensure stability?

• Answer: The compound is stable under normal laboratory conditions but should be stored in a tightly sealed container away from excessive heat (>40°C) and incompatible materials (e.g., strong oxidizing agents). Storage at 2–8°C in a dry environment is advised for long-term stability .

Q. What personal protective equipment (PPE) is required for safe handling?

• Answer: Use nitrile gloves, safety goggles, and lab coats to prevent skin/eye contact. Respiratory protection (e.g., N95 mask) is needed if dust generation occurs. Ensure fume hood use during weighing or dissolution .

Q. How should accidental exposure (e.g., inhalation or ingestion) be managed?

• Answer:

• Inhalation: Move to fresh air; administer oxygen if breathing is difficult. Avoid mouth-to-mouth resuscitation; use a pocket mask .
• Ingestion: Rinse mouth; do not induce vomiting. Seek immediate medical attention .
• Skin/Eye Contact: Flush with water for 15 minutes; remove contaminated clothing .

Advanced Research Questions

Q. How can enantiomeric impurities be resolved during synthesis?

• Answer: Chiral resolution techniques such as HPLC with a chiral stationary phase (e.g., amylose or cellulose derivatives) or enzymatic kinetic resolution are recommended. For example, use a Chiralpak® AD-H column with a hexane/isopropanol mobile phase (90:10 v/v) at 1.0 mL/min flow rate .

Q. What methodologies are suitable for quantifying trace impurities in this compound?

• Answer: High-resolution mass spectrometry (HRMS) coupled with reversed-phase HPLC (C18 column, 0.1% formic acid in water/acetonitrile gradient) provides sensitivity for detecting impurities at <0.1% levels. Validate with spiked recovery experiments .

Q. How can conflicting toxicological data (e.g., acute vs. chronic toxicity) be reconciled?

• Answer: Conduct tiered testing:

In vitro assays (e.g., Ames test for mutagenicity, hepatocyte cytotoxicity).

In vivo acute toxicity (OECD 423 guidelines, rodent models).

Subchronic studies (28–90 days) to assess dose-response relationships.
Cross-reference results with structurally similar compounds (e.g., tramadol derivatives) to identify potential metabolic pathways .

Q. What synthetic routes optimize yield while minimizing byproducts?

• Answer: A two-step approach:

Mannich Reaction: React cyclohexanol with 3-methoxybenzaldehyde and dimethylamine in ethanol at 60°C (yield: 65–70%).

Hydrochloride Salt Formation: Treat with HCl gas in anhydrous diethyl ether.
Purify via recrystallization (ethanol/water) to achieve >95% purity .

Q. How does the compound’s stability vary under different pH conditions?

• Answer: Perform accelerated stability studies:

• Acidic (pH 1–3): Degradation observed via hydrolysis of the methoxy group.
• Neutral (pH 7): Stable for >30 days at 25°C.
• Alkaline (pH 10–12): Rapid decomposition of the dimethylamino moiety.
  Use buffered solutions and monitor by NMR (¹H and ¹³C) to track structural changes .

Q. What computational methods predict biological activity (e.g., receptor binding)?

• Answer: Molecular docking (AutoDock Vina) with serotonin (5-HT) and norepinephrine (NET) transporters. Optimize force fields (AMBER) for ligand-receptor interactions. Validate predictions with in vitro radioligand binding assays .

Q. Data Contradiction Analysis

Q. How to address discrepancies in reported solubility values?

• Answer: Standardize solvent systems (e.g., USP buffers) and use nephelometry for turbidity measurements. Compare with PubChem data (CID 73806492) and validate via saturation shake-flask method .

Q. Why do different studies report varying metabolic half-lives?

• Answer: Variability arises from:
• Species Differences: Rodent vs. human liver microsomes.
• Enzyme Polymorphisms: CYP2D6 activity in metabolism.
  Use human hepatocytes and LC-MS/MS to standardize results .

Q. Methodological Tables

Table 1: Analytical Characterization Parameters

Table 2: Toxicity Testing Workflow

Pharmacological Profile

Tramadol acts as a μ-opioid receptor agonist (Ki = 2.1 μM) and inhibits the reuptake of norepinephrine (Ki = 0.79 μM) and serotonin (Ki = 0.99 μM), synergistically enhancing pain modulation . The (−)-enantiomer exhibits 10-fold greater norepinephrine reuptake inhibition than the (+)-enantiomer, while the latter is more potent in serotonin reuptake inhibition . This dual mechanism reduces typical opioid side effects like respiratory depression, which is only partially reversible by naloxone .

Adverse Effects

Key risks include seizures (dose-dependent) and serotonin syndrome , particularly with concurrent use of SSRIs or MAO inhibitors . Tramadol’s metabolite, O-desmethyltramadol , contributes to μ-opioid effects but lacks significant serotonergic activity .

Structural and Functional Analogues

Table 1: Comparative Analysis of Tramadol Hydrochloride and Analogues

Key Comparative Findings

Venlafaxine Hydrochloride

• Structural Difference: The 4-methoxyphenyl group and ethylamine chain in venlafaxine eliminate opioid activity, focusing solely on serotonin-norepinephrine reuptake inhibition (SNRI) .

O-Desmethyltramadol

• Metabolite Superiority : The hydroxyl substitution increases μ-opioid receptor affinity by ~70-fold compared to tramadol, enhancing analgesia but also respiratory depression risk .
• Therapeutic Limitation: Not used clinically due to unmanageable side effects, though it underscores tramadol’s prodrug nature .

Codeine and Hydrocodone

• Efficacy-Safety Trade-off : Codeine’s lower potency necessitates higher doses, increasing constipation risk, while hydrocodone’s κ-activity complicates its side effect profile .

Mechanistic Divergence

• Tramadol vs. Pure Opioids : Tramadol’s naloxone-resistant analgesia (attributable to NE/5-HT effects) differentiates it from morphine-like drugs, offering a wider therapeutic window .
• Enantiomer Specificity: The racemic mixture of tramadol ensures balanced NE/5-HT modulation, whereas pure enantiomers (e.g., levorphanol) lack this synergy .