Narcotic Analgesics - Organic Pharmaceutical Chemistry II - PDF

ceutical Chemistry I arma I c Ph ani rg O Dr. Ahmed Ali Al-Karmalawy Associate Professor of Medicinal Chemistry  [i] 4,5- [iv] 4-Phenylpiperidines and Epoxymorphinans 4-Anilidopiperidines [ii] M...

ceutical Chemistry I arma I c Ph ani rg O Dr. Ahmed Ali Al-Karmalawy Associate Professor of Medicinal Chemistry  [i] 4,5- [iv] 4-Phenylpiperidines and Epoxymorphinans 4-Anilidopiperidines [ii] Morphinans [v] Diphenylheptanes [iii] Benzomorphans [vi] Miscellaneous  [i] 4,5-Epoxymorphinans (1) Morphine: The prototype ligand for the µ-receptor. It contains 5 chiral centers and has 16 optical isomers (not 32 because of the restriction of C-9 to C-13 ethane amino bridge). Opium contains over 40 different alkaloids, and mostly the five structures: morphine (8%–17%), codeine (0.7%–5%), thebaine (0.1%–2.5%), papaverine (0.5%–1.5%), and noscapine (1%–10%). The pharmacological properties include analgesia, its primary use. Because it is poorly soluble in water, the sulfate salt is formed for oral, IV, and suppository use.  [i] 4,5-Epoxymorphinans (2) Codeine: Most commercial codeine is prepared from morphine by methylating the phenolic OH group. It is a monoacidic base and forms salts with acids, mostly the sulfate and the phosphate. The general pharmacological action of codeine is similar to that of morphine, but it possesses a lower analgesic potency and a lower addiction potential. Side effects include respiratory depression, miosis, constipation, nausea, itching, dry mouth, and drowsiness. Its role as an effective antitussive agent has been questioned. It is available in combination with either aspirin, ibuprofen, or acetaminophen for the treatment of moderate pain.  [i] 4,5-Epoxymorphinans (3) Heroin: It was first commercially synthesized in 1898 as an alternate analgesic to morphine. It is the 3,6 diacetylated form of morphine. With both OH groups protected as an ester, it can pass through the blood-brain barrier quicker than morphine and lead to the euphoric “rush” that becomes so addictive to addicts, especially after IV injection. It is not available as a prescription product in the United States, although it is available in some countries to treat pain associated with cancer and myocardial infarctions.  [i] 4,5-Epoxymorphinans (4) Hydromorphone: It is a synthetic derivative of morphine. Oxidation of the 6-OH of morphine decreased the potency. Reducing the 7,8-double bond of morphine increased the flexibility and resulted in a compound with slightly enhanced binding. It is approximately 5 times as potent as morphine. (5) Oxymorphone: It is the 14 beta-hydroxyl version of hydromorphone, analogous to the hydrocodone. The oral bioavailability is lower than that of hydromorphone. The addition of the OH group increases its binding affinity at the receptor as the injectable form of it is more potent than injectable hydromorphone.  [i] 4,5-Epoxymorphinans (6) Hydrocodone: It is the 3 methoxy version of hydromorphone. The loss of the 3-OH group yields a compound that is approximately 4 to 5 times less potent than hydromorphone, thus about equal to morphine. The protected 3-position has better brain penetration, and the 7,8-dihydro-6-keto C ring contributes to the increased binding of it to the µ-receptor. Like codeine, hydrocodone is marketed as an antitussive agent. It is available combined with the anticholinergic agent homatropine as a syrup and a tablet to discourage abuse. It is also marketed in combination with acetaminophen or aspirin for the treatment of pain.  [i] 4,5-Epoxymorphinans (7) Oxycodone: It is synthesized from thebaine. It is the 14 beta-hydroxyl version of hydrocodone. This additional functional group gives greater potency (1.5 times orally) than hydrocodone by increasing receptor affinity. It is marketed in combination with acetaminophen, aspirin, and ibuprofen.  [ii] Morphinans The morphinans were made by removing the E ring of morphine, the 4,5-ether bridge, to simplify the structure.  (1) Levorphanol: It is the levorotatory form of methorphan and is approximately 7.5 times more potent than morphine orally. It is an attractive alternate for patients that receive inadequate pain relief from morphine. It is available as oral tablet and a solution for injection. (2) Dextromethorphan: It is the dextrorotatory form of levorphanol with a methoxy group on the 3- position. It is available in more than 140 (OTC) cough and cold formulations. Its ability to antagonize the NMDA receptor has led to its use to treat phantom pain, diabetic neuropathy, and postoperative acute pain.  [iii] Benzomorphans Structural simplification of the morphine ring system further, by removing the C ring of the morphinan structure, yields the benzomorphans also referred to as the benzazocines. Pentazocine: The only benzomorphan in clinical use is pentazocine, which is prepared as the 2(R), 6(R), 11(R) enantiomer. It is a mixed agonist/antagonist displaying differing intrinsic activity at the opioid receptor subtypes. At the µ-receptor, it is a partial agonist and a weak antagonist. It is also an agonist at the κ-receptor, and this may be responsible for the higher percentage of patients that experience dysphoria with pentazocine versus morphine.  [iv] 4-Phenylpiperidines and 4-Anilidopiperidines Further structural simplification of the benzomorphan ring system, via removal of the B ring of the benzomorphans yields the 4-substituted piperidines. The resultant structures are flexible and, without the B ring locking the A ring in an axial position relative to the piperidine (D) ring, the A ring can exist in either an axial or an equatorial position.  (1) Meperidine: It was discovered in 1939 during a serendipitous screening of compounds being studied for antispasmodic activity. It was found to have low potency at the receptor compared with morphine (0.2%) but much higher penetration into the brain resulting in a compound with about 10% of the potency of morphine. It is metabolized to normeperidine which causes CNS excitation, presents clinically as tremors, twitches, “shaky feelings,” and multifocal myoclonus potentially followed by grand mal seizures. It is available in tablet, liquid, and injectable forms. The use of meperidine should be limited to those having true allergies to the morphine-type opioids.  (2) Diphenoxylate: It is a weak opioid agonist and is available combined with atropine (Lomotil), to dissuade abuse, for use as an antidiarrheal agent.  (3) Loperamide: It acts as an antidiarrheal by directly binding to the opiate receptors in the gut wall. It inhibits acetylcholine and prostaglandin release, decreasing peristalsis and fluid secretion thus increasing the GI transit time and reducing the volume of fecal matter. It is sufficiently lipophilic to cross the BBB, yet it displays no CNS-opioid effects. The reason that it is actively pumped out of the brain via the P- glycoprotein pump (MDR1). It is available as capsules for treatment of acute and chronic diarrhea.  (4) Fentanyl: When the 4-phenyl substituent of meperidine was replaced with a 4-aniline with a nitrogen connection, the potency increased. This led to the development of the 4-anilidopiperidine series of compounds. It was the first compound marketed and was found to be almost 500 times more potent than meperidine. The high lipophilicity of fentanyl gave it a quick onset, and the quick metabolism led to a short duration of action. The combination of potency, quick onset, and quick recovery led to the use of fentanyl as an adjunct anesthetic. In addition to the injectable formulation, it is available in a unique transdermal system (Duragesic). This formulation is beneficial to many chronic pain sufferers unable to take oral medication. Patches are replaced every 72 hours.  (4) Fentanyl: The SAR studies of the 4-phenylpiperidine analgesics found that the propionamide is the optimal chain length. Adding polar groups to the 4- piperidine carbon (CH2OCH3 in sufentanil and alfentanil, COOCH3 in remifentanil) increases potency. Substituting the N-phenethyl group with bioisosteres led to the development of fentanyl congeners alfentanil, sufentanil, and remifentanil.  [v] Diphenylheptanes (1) Methadone: It is a synthetic opioid approved for analgesic therapy and for the maintenance and treatment of opioid addiction. It is marketed as the racemate, although the opioid activity resides in the R-enantiomer (7–50 times more potent than the S-enantiomer). It may only be dispensed for the treatment of opioid addiction. Adverse effects including constricted pupils, respiratory depression, physical dependence, extreme somnolence, coma, cardiac arrest, and death. In addition, QT interval prolongation and torsades de pointes have been reported.  [vi] Miscellaneous Tramadol: It is an analgesic agent with multiple mechanisms of action. It is a weak µ- agonist. At recommended doses, it has minimal effects on respiratory rate, heart rate, blood pressure, or GI transit times. Structurally, tramadol resembles codeine with the B, D, and E ring removed. It is synthesized and marketed as the racemic mixture of two (the [2S, 3S] [-] and the [2R, 3R] [+]) of the four possible enantiomers. The (+) enantiomer is about 30 times more potent than the (-) enantiomer; however, racemic tramadol shows improved tolerability.  [vi] Miscellaneous Tramadol: Like codeine, tramadol is O-demethylated via CYP2D6 to a more potent opioid agonist having 200-fold higher affinity for the opioid receptor than the parent compound. It was initially marketed as nonaddictive, and a 3-year follow up study showed that the abuse potential is very low, but not zero. Mixed Agonist/Antagonist  (1) Nalbuphine: It resembles oxymorphone with a cyclobutyl methyl group on the nitrogen, equivalent to naloxone’s substitution. At low parenteral doses, it has an analgesic potency approximately two thirds that of morphine, and it has a similar degree of respiratory depression. The oral bioavailability of nalbuphine is only 12%, and the drug is only marketed as an injectable. The pharmacologic profile in animal studies includes agonist activity at the κ-receptor and antagonist activity at the µ-receptor. Clinical studies have shown that nalbuphine, and κ-agonists in general, may have better analgesic activity in female patients compared with male patients. Used as the sole opioid agent, to treat the pain of labor, cesarean section, dental extraction, hip replacement, and hysterectomy surgery.  (2) Butorphanol: Structurally, it is a morphinan and shares the same cyclobutyl methyl group on the nitrogen as nalbuphine. Like nalbuphine, it is an agonist at the κ-receptor but at the µ-receptor it is both a partial agonist and an antagonist. The parenteral injection is used for moderate to severe pain associated with orthopedic procedures, obstetric surgery, and burns. The nasal preparation (Stadol NS) is an effective analgesic for the relief of moderate to severe pain such as migraine attacks, dental, or other surgical pain.  (3) Buprenorphine: It is a semisynthetic, highly lipophilic opiate derived from thebaine. Pharmacologically, it is classified as a mixed µ-agonist/antagonist (a partial agonist) and a weak κ-antagonist. It has a high affinity for the µ-receptors (1,000 times greater than morphine) and a slow dissociation rate leading to its long duration of action (6–8 hours). A drug of interest for the treatment of opioid dependence. Early clinical studies showed that the oral bioavailability of it was low because of intestinal and liver metabolism. Therefore, a sublingual (SL) formulation (Subutex) was developed. A transdermal patch is available outside the United States for use in chronic pain. Opioid Antagonists  (1) Naltrexone: It is a pure opioid antagonist at all opioid receptor subtypes with the highest affinity for the µ-receptor. It is orally bioavailable and blocks the effects of opiate agonists for approximately 24 hours after a single dose of 50 mg. Theoretically, it should work well to treat opioid dependence but in clinical practice, patients have shown poor compliance and high relapse rates. It has also been studied to treat alcohol dependence with mixed results. To increase the compliance issues and effectively remove the “choice” of taking the antagonist, it was developed into an extended release injectable microsphere formulation for IM injection once a month (Vivitrol). Currently, Vivitrol is only indicated for the treatment of alcohol dependence.  (2) Naloxone: It is a pure antagonist at all opioid receptor subtypes. Structurally, it resembles oxymorphone except that the methyl group on the nitrogen is replaced by an allyl group. This minor structural change retains high binding affinity to the receptor, but no intrinsic activity. It is used to reverse the respiratory depressant effects of opioid overdoses. Neonates born to opioid-exposed mothers may be given IV naloxone at birth to reverse the effects of opiates.  (3) Nalmefene: It is a pure opioid antagonist that is the 6-methylene analog of naltrexone. It is available as a solution for IV, IM, or subcutaneous (SC) administration to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It has higher oral bioavailability (approximately 40%) than naloxone or naltrexone and is currently used as an oral treatment for pathological gambling and alcohol abuse.  (4) Methylnaltrexone: It is the methylated, quaternary form of naltrexone. The permanently charged nitrogen prevents the drug from crossing the BBB. Thus, it only acts as an antagonist at peripheral opioid receptors. It was approved in April 2008 to treat opioid-induced constipation in patients receiving palliative care. It is administered as a SC injection.