Opioid Receptors and Analgesics PDF

Opioid receptors and analgesics Dr. Muayyad S. Tahir PhD Medicinal chemistry 1 Introduction Analgesics can be categorized, according to their therapeutic use, into several drug classes: (a) the opioids (or narcotic analgesics), which play...

Opioid receptors and analgesics Dr. Muayyad S. Tahir PhD Medicinal chemistry 1 Introduction Analgesics can be categorized, according to their therapeutic use, into several drug classes: (a) the opioids (or narcotic analgesics), which play a major role in the relief of acute pain and in the management of moderate to severe chronic pain; (b) the NSAIDs and acetaminophen, which are the most widely used analgesic drugs for relieving mild to moderate pain and reducing fever. (c) the triptans (the antimigraine medications), which are specifically designed and targeted for acute and abortive treatment of migraine and cluster headaches. 2 Introduction (d) a new emerging class of analgesics known as analgesic adjuvants that include tricyclic antidepressants such as amitriptyline, anticonvulsants such as gabapentin and pregabalin, and topical analgesics such as lidocaine patches that can be used to treat neuropathic pains. 3 Introduction Origin of Pain Pain has been classified into three major types: physiological (nociceptive), inflammatory, and neuropathic. Physiological pain is the most common and is often caused by an injury to body organs or tissues. Inflammatory pain originates from an infection or inflammation as a result of the initial tissue or organ damage. Neuropathic pain is a chronic pain resulting from injury of the nervous systems. 4 5 Opioid receptors Opioid receptors are distributed throughout the brain, spinal cord, and peripheral tissues. The distribution of specific opioid receptor subtypes (μ, δ , and κ ) usually overlaps. All of the opioid receptors belong to the G-protein–coupled receptor class. When the receptor is activated, a portion of the G protein diffuses within the membrane and causes an inhibition of adenylate cyclase activity. The decreased enzyme activity results in a decrease in cyclic adenosine monophosphate (cAMP) formation. 6 Opioid receptors Then, the opening of voltage gated calcium influx channels is inhibited. This results in the hyperpolarazation of the nerve cell and decreased firing and release of pain neurotransmitters such as glutamate and substance P. 7 Opioid receptors THE μ-RECEPTOR Mu receptors are found primarily in the brainstem and medial thalamus. Endogenous peptides for the μ-receptor include endomorphin-1, endomorphin-2, and β-endorphin. Exogenous agonists for the μ-receptor include drug classes: 4,5- epoxymorphinan, morphinan, benzomorphan, 4-phenyl/4-anilido piperidines, and the diphenylheptanes. 8 Opioid receptors In general, agonists at the μ-receptor produce analgesia, respiratory depression, decreased gastrointestinal (GI) motility, euphoria, and the release of hormones. Agonists are also responsible for the addictive effects of the opioid analgesics. Most clinically used opioid drugs bind to the μ-opioid receptor. 9 Opioid receptors THE δ -RECEPTOR It is thought that ligands targeting these receptors may represent new leads for the treatment of schizophrenia, bipolar disorders, and depression. In humans, they are reported to have proconvulsive activity that may limit their use. 10 Opioid receptors THE к-RECEPTOR Kappa receptors are primarily found in the limbic, brain stem, and spinal cord. In clinical trials, most к-agonists produce dysphoria and thus may be less psychologically addicting but also less acceptable to patients. Some compounds with к-agonist activity (e.g., pentazocine, nalbuphine) are available. 11 Opioid receptors Clinical trials in humans found that spiradoline (к-agonist) did not produce analgesic effects within a dose range that did not also cause dysphoria, diuresis, and sedation. The selective к-agonist TRK-820 shows some promise for the treatment of uremic pruritus, the itch associated with dialysis. 12 SAR of morphine The prototype ligand for the μ-receptor is morphine. Morphine contains 5 chiral centers and has 16 optical isomers (not 32 because of the restriction of C-9 to C-13 ethanamino bridge). The only naturally occurring, active form of morphine is the levorotatory enantiomorph with the stereochemistry 5(R), 6(S), 9(R), 13(S), and 14 (R). The x-ray determined conformation of morphine is a “T” shape with the A, B, and E rings forming the vertical portion, and the C and D ring forming the top. 13 14 15 SAR of morphine It’s primary use for analgesia. For equivalent analgesic effect, the oral dose must be 3 times the intravenous (IV) dose to account for the morphine lost to first-pass hepatic metabolism. 16 SAR of Meperidine Meperidine 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. Meperidine is an agonist at the μ-receptor and a 300-mg oral or 75-mg IV dose is reported to be equianalgesic with morphine 30-mg oral or 10-mg IV dose. 17 SAR of Meperidine 18 SAR of Meperidine The 4-ethyl ester was found to be the optimal length for analgesic potency. Increasing or decreasing the chain length decreased activity. Structural changes that increase the potency of meperidine include the introduction of an m-hydroxyl on the phenyl ring, substituting the methyl on the N for a phenylethyl or a p-aminophenylethyl. 19 SAR of Meperidine Replacing the N-methyl with an N-allyl or N-cyclopropylmethyl group does not generate an antagonist, unlike the similar substitution of the morphine congeners. The duration of analgesia of meperidine may be shorter than the 3- to 4-hour half-life of the drug. This may necessitate frequent dosing to relieve pain, and thus the excessive metabolic formation of normeperidine. 20 SAR of Meperidine Normeperidine has been shown to cause central nervous system (CNS) excitation that presents clinically as tremors, twitches, and multifocal myoclonus followed by grand mal seizures. Patients at the greatest risk of developing normeperidine toxicity are those that are on high doses, long durations (greater than 3 days), have renal dysfunction, and those on CYP inducers. 21 SAR OF METHADONE Methadone (Dolophine) is a synthetic opioid approved for analgesic therapy and for the maintenance and treatment of opioid addiction. 22 SAR OF METHADONE It is a racemic mixture; the opioid activity resides in the R-enantiomer (7–50 times more potent than the S-enantiomer). Methadone may only be dispensed for the treatment of opioid addiction. Methadone is a μ-receptor agonist. The major metabolic pathway of methadone metabolism is via N- demethylation to an unstable product that spontaneously cyclizes to form the inactive 2-ethylidene-1,5-dimethyl-3,3- diphenylpyrrolidine (EDDP). 23 SAR OF METHADONE 24 SAR OF METHADONE Adverse effects of methadone include all of the standard opioid 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. 25 Benzomorphans Structural simplification of the morphine ring system, by removing the C ring of the morphinan structure, yields the benzomorphans also referred to as the Benzazocines. The active benzomorphans are those that have the equivalent bridgehead carbons in the same absolute configuration of morphine (carbons 9, 13, and 14 of morphine). The only benzomorphan in clinical use is pentazocine, which is prepared as the 2(R), 6(R), 11(R) enantiomer (Chemical Abstracts numbering). 26  Pentazocine is a mixed agonist/antagonist displaying differing intrinsic activity at the opioid receptor subtypes. At the μ- receptor, pentazocine is a partial agonist and a weak antagonist. Pentazocine is also an agonist at the к- receptor, and this may be responsible for the higher percentage of patients that experience dysphoria with pentazocine versus morphine. 27  Pentazocine is available in a 50-mg tablet along with a low dose of the antagonist naloxone 0.5 mg (Talwin NX). 28 Questions? 29