PHARMACY 312 MSK Lecture 3 Medchem of opioids and NSAIDs 2024.pdf

Medicinal Chemistry of opioids BPHARM312 and NSAIDs Musculoskeletal module DR LYDIA LIEW [email protected] LEARNING OBJECTIVES Drugs for treatment of pain  Structure-activity relationship of opioids  Identify key structural features for opi...

Medicinal Chemistry of opioids BPHARM312 and NSAIDs Musculoskeletal module DR LYDIA LIEW [email protected] LEARNING OBJECTIVES Drugs for treatment of pain  Structure-activity relationship of opioids  Identify key structural features for opioid analgesic activity  Identify structural differences between drugs within this class  Describe how different functional groups affect activity (increases or decreases potency, metabolism etc.)  Structure-activity of nonsteroidal anti-inflammatory drugs (NSAIDs)  Describe the role of different COX enzyme isoforms  Identify structural features in NSAIDs that gives rise to COX-2 selectivity OPIOIDS Endogenous opioid peptide ligands  Opioid receptor agonists  Opioid receptor antagonists Distribution of opioid receptors  Human brain  Spinal cord  Peripheral tissues Chan et al. (2017) Trends Pharmacol. Sci., 38(11), 1016-1037. OPIOID RECEPTORS G-protein coupled receptors (GPCR) Seven transmembrane (TM) domains Plays a role in the modulation of pain Three major classes of opioid receptors  μ-receptor (MOR)  κ-receptor  δ-receptor μ-OPIOID RECEPTOR (MOR) Agonists of μ-opioid receptor (MOR) Most clinically relevant Produces analgesic effects, respiratory depression, decreased gastrointestinal mobility, euphoria, feeding and release of hormones μ-OPIOID RECEPTOR (MOR) Agonist binding Molecular switch Chan et al. (2017) Trends Pharmacol. Sci., 38(11), 1016-1037. OPIOIDS Two key structural features for opioid analgesic activity  Aromatic A ring  Basic nitrogen Necessary components for activity BUT alone are not sufficient for MOR opioid activity HO 3 A Other pharmacophoric groups are required B O E H 13 9 D N 14 C HO 6 Morphine OPIOIDS - MORPHINE Isolated from opium by German pharmacist in 1806 Prototype μ-opioid receptor agonist primarily used for its analgesic effects  Other μ-opioid receptor agonists are compared to morphine Extensively metabolised in the liver HO  Sites of metabolism: N-demethylation and 3/6 glucuronidation 3 A Poorly soluble in water (1g/5L @25°C) B E H Administered as a sulfate salt O 13 9 D N 14 C HO 6 Morphine STRUCTURE-ACTIVITY RELATIONSHIP OF MORPHINE ANALOGUES Equianalgesic dose of morphine analogues O O HO O 3 A B O H O E H O H 13 9 N D N 14 N C HO HO 6 O Codeine Morphine Heroin oral = 200 mg oral = 30 mg O oral = 15 mg HO O O HO HO O OH O H O OH O OH O H N N N N N O O O O O Naloxone Hydrocodone Oxycodone Oxymorphone Hydromorphone (antagonist) oral = 30 mg oral = 20 mg oral = 10 mg oral = 7.5 mg OPIOIDS - CODEINE HO 3 A B Similar pharmacological action to morphine O E 13 H 9 D N Methylated at the 3-OH position makes the molecule more hydrophobic 14 C  Increases the ability on the drug to cross the blood brain barrier HO 6  Lower analgesic potency than morphine Morphine  Lower addiction potential O 3 Prodrug: Codeine O-demethylation by CYP2D6 to give morphine Genetic polymorphism O H Poor metabolisers within the population N HO Codeine OPIOIDS - OXYCODONE HO 3 A B Methylated at the 3-OH position makes the molecule more hydrophobic O E 13 H 9  Decreases activity D N 14 Hydroxylated at the 14 position HO 6 C  This functional group increases affinity for MOR Morphine  Increases activity O Reduced double-bond at positions 7and 8 (7,8-dihydro)  Increased flexibility of compound, improved binding O OH  Increases activity (x5 more potent than morphine) 14 N Oxidation at the 6 position 6 8  Decreases activity, but is offset by increased flexibility with 7,8-dihydro O 7 Oxycodone STRUCTURE-ACTIVITY RELATIONSHIP OF MORPHINE ANALOGUES Equianalgesic dose of morphine analogues O O HO O 3 A B O H O E H O H 13 9 N D N 14 N C HO HO 6 O Codeine Morphine Heroin oral = 200 mg oral = 30 mg O oral = 15 mg HO O O HO HO O OH O H O OH O OH O H N N N N N O O O O O Naloxone Hydrocodone Oxycodone Oxymorphone Hydromorphone (antagonist) oral = 30 mg oral = 20 mg oral = 10 mg oral = 7.5 mg OPIOIDS – TRAMADOL O A B O E H Structurally similar to codeine D N  B,D and E rings removed C HO Patients allergic to codeine should not be prescribed tramadol Codeine Tramadol is synthesised and marketed as a racemic mixture O The R-enantiomer is more potent than the S-enantiomer at MOR Racemate is more tolerated OH N R-Tramadol OPIOIDS – TRAMADOL Additionally, the R-enantiomer responsible for inhibition of serotonin reuptake S-enantiomer responsible for inhibition of norepinephrine reuptake The major O-demethylated metabolite of tramadol is proconvulsive  Should not be given to patients with epilepsy O O OH HO N N R/S-Tramadol OPIOIDS – FENTANYL 4-Substituted piperidines, structurally similar to morphine  B,C and E rings removed HO 3 A B O E H O N 13 9 N N 14 D O O N C HO 6 Morphine Meperidine Fentanyl OPIOIDS – FENTANYL Alkyl chains gives the compound high lipophilicity allowing it to cross BBB  Increased potency - quick onset  Quickly metabolised - short duration of action  Adjunct anesthetic HO 3 A B O E H O N 13 9 N N 14 D O O N C HO 6 Morphine Meperidine Fentanyl  HO OPIOIDS – METHADONE 3 A B O E H 13 9 D N Long acting μ-receptor agonist 14 C HO 6 Used for rehabilitation in opioid addicts Morphine O N Methadone OPIOIDS – METHADONE Metabolism of methadone is important for its MOA O O spontaneous CYP450 N N N Methadone Normethadone Inactive Build up of metabolites are responsible for the long duration of action O Alcohol dehydrogenase HO CYP450 HO CYP450 HO N N NH NH2 α-Methadol α−Dinormethadol Methadone α-Normethadol Active Active OPIOID RECEPTOR ANTAGONIST -NALOXONE HO 3 A Pure antagonist at all opioid receptor subtypes O E H B 9 13 Competes with agonists for receptor binding sites 14 D N C Slightly selective for MOR HO 6 Morphine Increasing the N-substituent to 3-5 carbons  Produces antagonist effects HO  Larger groups (eg. phenylethyl) returns agonist activity Minor structural change O OH  retains binding affinity to MOR  but has no intrinsic activity N O Naloxone (antagonist) NSAIDS NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Widely prescribed pain medications Effective for mild to moderate pain relief Cyclooxygenase (COX) inhibitors  Membrane phospholipids CYCLOOXYGENASE Phospholipase A2 Arachidonic acids Cyclooxygenase Proinflammatory prostaglandins Pain, inflammation, fever Ulrich et al. (2006) Nat. Rev. Cancer, 6, 130. COX INHIBITORS Two cyclooxygenase (COX) isoforms HN O  COX-1 constitutively expressed  For normal physiological function in the gastrointestinal tract, kidneys  COX-2 inducible isozyme  Induced upon injury, inflammation or infection Non-selective COX inhibitors OH  Side effects in the GI tract and affect renal function Acetaminophen COX-3? COX-2 selective inhibitors  Improved safety profile ARACHIDONIC ACIDS Natural substrates for cyclooxygenase (COX-1 and COX-2) VAL509 Active site Arachidonic acid OH O ARG NON-SELECTIVE COX INHIBITORS Nonselective inhibitors have access to the binding channels of both isoforms. Grosser et al. (2006) J. Clin. Investig. 116, 4-15. NON-SELECTIVE COX INHIBITORS O O O HO HO S-Naproxen R/S-Ibuprofen O O O HO Grosser et al. (2006) J. Clin. Investig. 116, 4-15. Aspirin COX-2 SELECTIVE INHIBITORS The more voluminous residues in COX-1 (Ile434, His513, and Ile532) obstruct access of the bulky side chains of COX-2 inhibitors. Grosser et al. (2006) J. Clin. Investig. 116, 4-15. COX-2 SELECTIVE INHIBITORS Celecoxib  First COX-2 selective inhibitor introduced into the market (1998) Blocks the inducible COX-2 isozyme Fewer gastrointestinal complications H 2N O VAL509 S O N N Celecoxib ARG F F F COX-2 SELECTIVE INHIBITORS O OH O N Cl OH N S H H N N S O O Cl Meloxicam Diclofenac H2 N O O S NH S O O O O S O N N O O N O F F F Celecoxib Parecoxib Rofecoxib Grosser et al. (2006) J. Clin. Investig. 116, 4-15.  Membrane phospholipids CYCLOOXYGENASE Phospholipase A2 Arachidonic acids COX-2 selective inhibitors tip the Cyclooxygenase natural balance between prothrombotic (TxA2) and antithrombotic prostacyclin (PGI2) – increases the possibility of Proinflammatory prostaglandins thrombotic cardiovascular event Pain, inflammation, fever Ulrich et al. (2006) Nat. Rev. Cancer, 6, 130. Warner et al. (1999) Proc. Natl. Acad. Sci. USA, 96, 7563-7568. Rao & Knaus (2008) J. Pharm. Pharmaceut. Sci., 11, 81s-110s. SELECTIVITY PROFILES OF NSAIDS Gan et al. (2010) Curr. Med. Res. Opin. 26, 1715-1731. NON-SELECTIVE COX INHIBITOR - ASPIRIN Reduces risk of thrombosis Binds irreversibly to COX-1 by acetylating Ser530 Blocks thromboxane A2 synthesis O O O HO Aspirin Rao & Knaus (2008) J. Pharm. Pharmaceut. Sci., 11, 81s-110s. SELECTIVE COX-2 INHIBITOR - ROFECOXIB Increases thrombotic cardiovascular event Selective COX-2 inhibitors do not have effect on thromboxane A2 function Decreases prostacyclin production (anti-thrombotic) O S O O O Rofecoxib Rao et al. (2008) J. Pharm. Pharmaceut. Sci., 11, 81s-110s. RISK-BENEFIT EVALUATION Selective COX-2 inhibition  Reduces the risk of gastrointestinal complications  Increases the risk of thrombotic cardiovascular event: myocardial infarction, stroke Consider: Patients with rheumatoid arthritis are often treated with glucocorticoids  More risk of GI complications  Other ways to reduce GI complications: avoid high-dose treatment, co-treatment with proton-pump inhibitor Patients predisposed to cardiovascular event, impaired renal function BIBLIOGRAPHY 1) Wilson, C. O.; Gisvold, O.; Beale, J. M.; Block, J. H. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th ed., International ed. / edited by John M. Beale, John Block..; Textbook of organic medicinal and pharmaceutical chemistry; Philadelphia, Pa. ; London : Lippincott Williams & Wilkins 2010., 2010. (2) Williams, D. A.; Lemke, T. L. Foye’s Principles of Medicinal Chemistry, 5th ed..; Lemke, T. L., Series Ed.; Principles of medicinal chemistry; Philadelphia, Lippincott Williams & Wilkins copyright 2002., 2002. (3) Ulrich, C. M.; Bigler, J.; Potter, J. D. Non-Steroidal Anti-Inflammatory Drugs for Cancer Prevention: Promise, Perils and Pharmacogenetics. Nat. Rev. Cancer 2006, 6, 130. https://doi.org/10.1038/nrc1801. (4) Chan, H. C. S.; McCarthy, D.; Li, J.; Palczewski, K.; Yuan, S. Designing Safer Analgesics via Mu-Opioid Receptor Pathways. Trends Pharmacol. Sci. 2017, 38 (11), 1016–1037. https://doi.org/10.1016/j.tips.2017.08.004. (5) Grosser, T.; Fries, S.; FitzGerald, G. A. Biological Basis for the Cardiovascular Consequences of COX-2 Inhibition: Therapeutic Challenges and Opportunities. J. Clin. Invest. 2006, 116 (1), 4–15. https://doi.org/10.1172/JCI27291. (6) Gan, T. J. Diclofenac: An Update on Its Mechanism of Action and Safety Profile. Curr. Med. Res. Opin. 2010, 26 (7), 1715–1731. https://doi.org/10.1185/03007995.2010.486301. (7) Warner, T. D.; Giuliano, F.; Vojnovic, I.; Bukasa, A.; Mitchell, J. A.; Vane, J. R. Nonsteroid Drug Selectivities for Cyclo-Oxygenase-1 Rather than Cyclo-Oxygenase-2 Are Associated with Human Gastrointestinal Toxicity: A Full in Vitro Analysis. Proc. Natl. Acad. Sci. 1999, 96 (13), 7563–7568. https://doi.org/10.1073/pnas.96.13.7563. (8) Rao, P.; Knaus, E. E. Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond. J. Pharm. Pharm. Sci. 2008, 11 (2), 81s–110s. https://doi.org/10.18433/J3T886.