1. Davis MDCH 5210 - Analgesics (Opioids) 2005 1 Altered behavioral response to pain and diminished ability to perceive pain impulses without loss of consciousness. Opioid Analgesic Actions: Analgesia Decreased G.I. Motility Respiratory Depression Euphoria Classes of Analgesics: Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the periphery as anti-inflammatories with some CNS activity as well. Narcotic/Opioids – Analgesic action is in the CNS. Morphine is the prototype (From “Morpheus” Greek god of dreams). Opium is the juice from the poppy and has been used for thousands of years to relieve pain. Morpheus - son of Hypnos Analgesia

2. Davis MDCH 5210 - Analgesics (Opioids) 2005 2 "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." Thomas Sydenham (1624 - 1689) 17th century engraving of man in Eastern dress collecting juice from the buds of poppy plants He was among the first to describe scarlet fever, differentiating it from measles and naming it, and to explain the nature of hysteria and St. Vitus' dance (Sydenham's chorea). Sydenham introduced laudanum (alcohol tincture of opium) into medical practice, was one of the first to use iron in treating iron-deficiency anemia, and helped popularize quinine in treating malaria. Derided by his colleagues, Sydenham benefited immensely from a consequent detachment from the speculative theories of his time Thomas Sydenham

3. Davis MDCH 5210 - Analgesics (Opioids) 2005 3 Early victims of the War On Drugs. A battle-scene from the First Chinese Opium War (1839-42) War On Drugs.

4. Davis MDCH 5210 - Analgesics (Opioids) 2005 4 Small peptides.  -endorphin is a 31 amino acid peptide. Examples: Tyr – Gly –Gly – Phe – Met ( Met Enkephalin) Tyr – Gly –Gly – Phe – Leu ( Leu Enkephalin) Endogenous Opioids Endorphins and Enkephalins

5. Davis MDCH 5210 - Analgesics (Opioids) 2005 5 Similar activity to the opioids (analgesia) Similar addiction and withdrawal effects Enkephalins are antagonized by opioid antagonists (same receptor) Enkephalins are rapidly inactivated by specific peptidases in the brain. Details of Enkephalin Mechanism Enkephalinergic system exists to modulate pain. Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits nerve cell activity. Opioids also bind the enkephalin post-synaptic receptors. Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin or exogenous opioids. Opioid binding to the “auto-receptor decreases enkephalin release, this results in tolerance, Enkephalin Properties:

6. Davis MDCH 5210 - Analgesics (Opioids) 2005 6 Enkephalinergic Neurons

7. Davis MDCH 5210 - Analgesics (Opioids) 2005 7 Second Messenger Effects Opioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The physiological response is to make more enzyme to compensate. Tolerance develops. When opioids are removed, an excess of AC is available and now active, overstimulation produces withdrawal. Opioid antagonists don’t cause withdrawal symptoms in naive subjects. Enkephalin SAR L-tyrosine is required along with a terminal NH 2. D-tyrosine is inactive Phe is very important, partial or full loss of activity occurs upon substitution D-amino acids at other positions, particularly the Gly’s decrease hydrolysis and therefore increase potency. D-amino acids and bulky amino acids affect activity and may increase receptor selectivity Rigid analogs are useful for assessing preferred conformations and may be more selective for different receptors. Second Messenger Effects - Enkephalin SAR

8. Davis MDCH 5210 - Analgesics (Opioids) 2005 8 All bind morphine and endogenous enkephalins, all are antagonized by naloxone  is the analgesic receptor.  2 subtype is associated with respiratory depression and with GI receptors.  may be the antitussive receptor for codeine and related compounds. The antitussive actions of  and  specific agonists are antagonized by naloxone. However dextromethorphan sites don’t bind codeine, and binding at these sites (likely  sites) are not antagonized by naloxone. Therefore, there are at least two antitussive receptors. J. Pharm. And Exp. Therapeutics (2000) 292, 803-809  is also analgesic. Binding site of several mixed agonist/antagonist compounds. Pentazocine – agonist at , antagonist at  Buprenorphine – partial agonist at  (slowly dissociates), antagonist at  Butorphanol – agonist at , antagonist at  Analgesic Receptors 

9. Davis MDCH 5210 - Analgesics (Opioids) 2005 9  agonists produce psychotomimetic/dysphoric side effects similar to those seen with the  receptor agonist PCP. High doses of pentazocine have this effect.  and  receptors are not analgesic on their own, but specific  agonists do cause analgesia. Nature (1996) 383, p.759; pp.819-823.  knockout does not produce analgesia with morphine, Perhaps  receptors interact.  binding could induce activity in  receptors. Other points:  (MOR) knockouts are fully functional, no adverse side effects. Conclusion: opioid system is not active under normal resting conditions. That’s why you don’t get addicted to your own enkephalins. Receptors - continued

10. Davis MDCH 5210 - Analgesics (Opioids) 2005 10 Opioid receptors and trans-membrane helices

11. Davis MDCH 5210 - Analgesics (Opioids) 2005 11 Mahalaxmi Aburi et al. Protein Sci 2004; 13: 1997-2008 Figure 3. The starting configuration for the simulation of the hDOR in a lipid bilayer Delta Opioid Receptor Simulation

12. Davis MDCH 5210 - Analgesics (Opioids) 2005 12 Opioids have excitatory effects in multiple regions of the nervous system. Excitation by opioids is generally attributed to inhibition of inhibitory pathways (disinhibition). However, recent studies indicate that opioids can directly excite individual cells. These effects may occur when opioid receptors interact with other G protein coupled receptors, when different subtypes of opioid receptors interact, or when opioids transactivate other receptors such as receptor tyrosine kinases. Changes in the relative level of expression of different receptors in an individual cell may therefore determine its functional response to a given ligand. This phenomenon could represent an adaptive mechanism involved in tolerance, dependence and subsequent withdrawal. From inhibition to excitation: Functional effects of interaction between opioid receptors Life Sciences Volume 76,Life Sciences Volume 76,, (2004), Pages 479-485 Receptor Communication

13. Davis MDCH 5210 - Analgesics (Opioids) 2005 13 ABSTRACT: Despite tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes, mu, delta and kappa, whose genes have been cloned. Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the mu-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system in these animals. Investigation of the behavioural effects of morphine reveals that a lack of mu receptors abolishes the analgesic effect of morphine, as well as place- preference activity and physical dependence. We observed no behavioural responses related to delta- or kappa-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the mu-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action. Nature. (1996) 383:819-23. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.

14. Davis MDCH 5210 - Analgesics (Opioids) 2005 14 SAR-SAR-SAR-SAR-SAR-SAR 1.Modifications at the phenolic OH (3-position). 2.Decrease analgesic potency, increase antitussive activity. Numbering of morphine is based on phenanthrene. The important positions, 3,6,7,8,14 are indicated. 1/7 as active compared to morphine for pain. Not a better antitussive. Codeine only binds 1/3000 the affinity of morphine to  receptor. Analgesic action is due to morphine. SAR - 1

15. Davis MDCH 5210 - Analgesics (Opioids) 2005 15 2. Modifications at the alcoholic OH ( 6 position). Substituents increase potency by increasing liposolubility. Increased potency and addiction. SAR - 2

16. Davis MDCH 5210 - Analgesics (Opioids) 2005 16 3. Modifications of both 3 and 6 positions (hydroxyls). Greater euphoria, higher addiction liability. Probably metabolized to 6-O-acetate then morphine in CNS. HEROIN A powerful remedy for coughs SAR - 3

17. Davis MDCH 5210 - Analgesics (Opioids) 2005 17 4A. Reduction of the 7,8 double bond. Compounds with same Substituents at R and R 1 and a reduced double bond have the same potency as morphine. “dihydromorphine”, “dihydrocodeine.” 4B. Reduction of the 7,8-double bond and oxidation of 6-OH to carbonyl. SAR - 4

18. Davis MDCH 5210 - Analgesics (Opioids) 2005 18 5. Hydroxylation of C-14, reduction of 7,8-double bond, oxidation of 6-OH. Generally increases potency. 6. Modifications at Nitrogen. 2 o N << 3 o ; 4 o Nitrogen is inactive. -N(R) groups larger than CH 3 produce antagonists. Nalorphine will compete with more potent agonists to cause withdrawal. SAR - 5

19. Davis MDCH 5210 - Analgesics (Opioids) 2005 19 7. Substitute at Nitrogen plus reduce 7,8-double bond, hydroxylate C-14, oxidize C6-OH to the carbonyl. Etorphine (an oripavine) 200 x Morphine, Approx. 8000 x Morphine in animals. Puts elephants to sleep. SAR - 6

20. Davis MDCH 5210 - Analgesics (Opioids) 2005 20 We need analgesics with less respiratory depression that are also less addictive. Morphinans. levorphanol (Levo-Dromoran) (-) isomer is an active analgesic, 5 x morphine (+) isomer is an active antitussive (dextrorphanol) and a poor analgesic (+) or (d) dextromethorphan Antitussive activity similar to codeine, no analgesic activity, no addiction liability. butorphanol (Stadol) 4 x morphine as agonist 1 x morphine as antagonist -low(er) addiction liability “ better for acute pain ” SAR - 7

21. Davis MDCH 5210 - Analgesics (Opioids) 2005 21 Meperidine Morphine SAR - 8

22. Davis MDCH 5210 - Analgesics (Opioids) 2005 22 4-phenyl piperidine SAR. Phenyl and piperidine rings are required. 3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases potency (fentanyl). You can’t make an antagonist by substituting the nitrogen. Addition of a meta hydroxyl to the aromatic ring increases potency and addiction (analogous to morphine) C-4 is usually quaternary. Alkyl esters are common for this class. Placing a nitrogen between the rings increases potency (fentanyl again) Properties of Phenylpiperidines. Bemidone – 3 x Meperidine  -Prodine (Nisentil) – 2 x Meperidine. Not used anymore Fentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration. Used as an analgesic and also as an anesthetic either with or without droperidol. (About 500 x Meperidine analgesic potency). Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can be dispensed with Atropine Loperamide (Imodium) – Polar groups decrease intestinal absorption and eliminate CNS activity. Inhibits GI muscle contraction by interaction with opioid receptor. SAR - 9

23. Davis MDCH 5210 - Analgesics (Opioids) 2005 23 SAR - 10

24. Davis MDCH 5210 - Analgesics (Opioids) 2005 24 3,3- Diphenylpropyl amines. Methadone 1x morphine less sedative longer acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent heroin withdrawal Propoxyphene d isomer (Darvon) – analgesic with 1/2 the potency of codeine l isomer (Novrad) – antitussive action only. SAR - 11

25. Davis MDCH 5210 - Analgesics (Opioids) 2005 25 Fentanyls Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100  g/h) Therapeutic index=400, morphine = 70 Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000 Sufentanil - 5-10x Fentanyl, used for heart surgery. Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.

26. Davis MDCH 5210 - Analgesics (Opioids) 2005 26 SAR - 12

27. Davis MDCH 5210 - Analgesics (Opioids) 2005 27 SAR - 13