Chapter 2.5. Analgesics 镇痛药

1. An analgesic (painkiller) is a drug used to relieve pain and to achieve analgesia. This derives from Greek an-, "without", and -algia, "pain". Chapter 2.5. Analgesics 镇痛药

2. The Pain can be: Physiologial----hurt Inflammatory----disease Neuropathic---nerve damage Levels or categories of pain acute, chronic, cancer, arthropathy (e.g., arthritis) neuropathic and diabetic pain Classes of pain drugs opioids nonsteroidal anti-inflammatory drugs (NSAIDs) acetaminophen

3. Opiates and morphinomimetics Morphine and is the principal active agent in opium. The word "morphine" is derived from Morpheus, the God of dreams in Greek mythology. Opium poppy (papaver accae) -from juice of immature fruit At least 25 alkaloids in poppy -content of morphine is the highest, and it is the component that has analgesic effect

4. Morphine, like other opiates, acts directly on the central nervous system (CNS) to relieve pain. Morphine is highly addictive. 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

5. Development and Timeline Clarification of ab- solute configuration Extraction & separation of morphine Confirmation of molecular form Clarification of chem. structure Total synthesis Morphine was first isolated in 1803 by Derosne, but the credit generally goes to Serturner ( 1803), who first called attention to its basic properties.

6. Natural morphine is L-isomer. There are five chiral center: C-5, C-6, C-9, C-13 and C-14

7. Properties of Morphine Amino-N: basic--form salt with acid, in China it is HCl salt • Phenolic-OH: • acidic, pKa: 9.9--dissolve in NaOH • oxidation---sensitive to air, light

8. When heated to 140 oC under pressure with 35% HCl, morphine loses a molecular of water and yield Apomorphine, one of the most effective, prompt (10-15 minutes), and safe emetics in used today. Morphine Apomorphine

9. SAR of Morphine N-CH3-----N-CH: activity decrease by 95% N-CH3-----CH2CH2C6H5: activity increase 14-fold Nuclear substitution: Effects varies saturation increases potency, dihydromorphine, codeine potency increased if modified, such as ether, ester. free OH-essential, potency decreased if modified essential, potency decreased if modified

11. Heroine (海洛因）

12. Codeine Morphine • 20% of the analgesic effect of morphine • less addictive • 3. One of the best antitussive drugs

13. Pethidine (INN), Meperidine (USAN) (盐酸哌替啶) Dermol In 1938, Eisleb ans Schaumann reported a simple piperdine derivative, which possess analgesic effect. The compound was prepared as an antispasmodic. During the test, the mice had a peculiar erection of the tail (Straub reaction), which is characteristic of morphine. Methyl-4-phenyl-4-piperidine-carboxylic acid ethyl ester hydrochloride (Ethyl-1-methyl-4-phenylpiperidine-4-carboxylate) 1-甲基-4-苯基-4-哌啶甲酸乙酯盐酸盐 This discovery stimulated intensive researches for analgesics with structures not closely related to morphine.

14. Analogues that are structurally similar to A, D rings Morphine Pethidine

15. Chemical synthesis of Pethidine Ethylene oxide

16. Properties of Pethidine Stable at air ( HCl salt), easily absorb water It is hydrolyzed at acidic conditions (ester)

17. Metabolism of Pethidine It is metabolized in the liver Demethylpethidine Pethidine carboxylic acid Demethyl pethidine carboxylic acid

18. Derivatives of Pethidine anileridine fentanyl alphaprodine

19. Endogeneous analgesic substance In 1973, scientists from Sweden and USA announced the finding of morphine receptors inside animal’s brain • In 1974, two peptides with morphine-like analgesic effects were isolated from mammal’s brain. They were called Enkephalin: • H-Tyr-Gly-Gly-Phe-Leu-OH • H-Tyr-Gly-Gly-Phe-Met-OH After that, lots of endogeneous peptide with analgesic effect were obtained from hypophysis, cerebra, blood of human beings and animals. These peptides were named Endorphins

21. H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) (Dmt = 2',6'-dimethyltyrosine) DALDA and [Dmt1]DALDA

22. Long-lasting antinociceptive effect of[Dmt1]DALDA administered i.t. The long duration of action of [Dmt1]DALDA may be explained by the high stability of this peptide against enzymatic degradation and by its polar character, which slows down its diffusion out of the subarachnoid space and thus prevents significant systemic absorption.

23. Nomenclature of TIPP-NH2 Analogs TIPP-NH2: H-Tyr-Tic-Phe-Phe-NH2 DIPP-NH2: H-Dmt-Tic-Phe-Phe-NH2 DIPP-NH2[]: H-Dmt-Tic[CH2-NH]Phe-Phe-NH2 Tic = tetrahydroisoquinoline-3-carboxylic acid Dmt = 2',6'-dimethyltyrosine

24. 3 3 [ H]DAMGO [ H]DSLET selectivity ratio m d m d a a K [nM] K [nM] K / K i i i i a Mean of three determinations ± SEM Opioid Receptor Binding Assays of Mixed m Agonist/d Antagonists Compound TIPP - NH2 78.8 ± 7.1 3.00 ± 0.15 26.3 ± DIPP - NH ± 10.1 1.19 0.11 0.118 0.016 2 Y ± ± 2.11 DIPP - NH2 [ ] 0.943 0.052 0.447 0.007

25. SAR of analgesics methadone pethidine pentazocine morphine About 7.5 ~ 8.5 Å 1、Flat structure Site for anion 2、site for anion 6.5 Å Electronic center 3、cavity with suitable direction Cavity fitted with piperidinyl Flat area for aromatic ring Key to lock mechanism of receptor-ligand for rigid compound

26. Zpperform combination of ligand to receptor for flexible molecules The active conformation of methioenkephalin H-Tyr-Tic-Aladan-Phe-OH Conformer number 4 Delta E = 1.1 kcal/mol Above minimum Overlap with naltrindole