Chemistry of natural product Presentations.pptx

UNIT-1 MPharm (Pharmaceutical Chemistry)

1. MORPHINE INTRODUCTION Morphine was isolated from raw opium in 1805 by a German pharmacologist, Friedrich Wilhelm Adam Serturner . It is important among the opium alkaloid. The amout being nearly 3-23% . The other two closely related alkaloids are codeine and thebaine Due to the presence of phenanthrene nucleus these are also known as phenanthere alkaloid . Morphine is a natural opium alkaloid. It is a dried extract obtained from the capsules of the poppy plant known as papaver somniferum . It requires approximately 10 kg of raw opium to produce 1 kg of morphine. Uses of Morphine : Analgesia General anesthetic Cough suppressant Anti-diarrheal Pre-operative medication Post-operative medication

2. SOURCE: O pium or gum opium poppy or poppy capsules It is obtainted from dried latex of unripe capsules of papavarine species(by Vertical incisions 0.1 to 0.5 mm depth) . Papavarine sominiferum P . bractatum P . oriantale P . rhoeaes Commercial Varieties: Turkis opium Indian opium Chainese opium Russian opium

3. Properties and Uses:- Morphine is colorless prism . M.Pt :254 O C. Bitter in taste . Levo rotatory . Insoluble in water, little soluble in benzol, ether , chloroform sufficiently soluble in alcohol and alkali solution . Used as analgesic and sedative . Depressant action on various parts of the nervous system but habit forming. Diacetyl derivative of mophine- heroin (more habit forming than morphine) . Codeine sulfate less effective analgesic and antitussive causes addiction . Thebaine little medicinal values and produces convulsions .

4. MECHANISM OF ACTION Morphine binds to opiate receptors that control passage of Ca2+ and K+ through channels which in turn control acetylcholine (nerve transmitter) flow across synapses

5. Structural Area Relationship (SAR) of MORPHINE

6. SAR of MORPHINE : A aromatic ring B-cyclo hexane C-cyclo hexane D-pyridine E-tetra hydrofuran At 3,6 position,-OH groups:- Conversion of 3-OH to 3-methoxy gives codeine-decreases activity upto 15% of morphine Conversion of 6-OH to 6-methoxy gives heterocodeine- increases 6 fold activity Of morphine Oxidation of 6-OH gives ketone –decreases the activity O NCH3 HO HO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 A B C D E Note:- absence of 7,8 double bond in morphine --- decreases the activity 37% Absence of double bond and presence of ketone ----increases the activity

7. CHEMISTRY OF MORPHINE 1. SAR- The Phenol Moiety • Codeine is metabolised in the liver to morphine. • The activity observed is due to morphine. • Codeine is used for mild pain and coughs • Weaker analgesic but weaker side effects. Masking phenol is bad for activity

8. 2. SAR- The 6-alcohol Morphine Hydromorohine Desomorphine •Activity increases due to reduced polarity •Compounds cross the blood brain barrier more easily •6-OH is not important for binding •Oxidation , coupled with reduction of 7,8 C=C, increases activity

9. 3. SAR - Double bond at 7,8 Dihydromorphine Increased activity The DOUBLE BOND (alkene group) is not important to binding

10. 4. SAR- Replacement of N-CH 3 • Morphine also has a methyl group attached to a nitrogen atom. If this methyl group is replaced by a propenyl group, an antagonist of morphine called nalorphine is formed. NALORPHINE

11. CODEINE •Codeine is available as a sulfate and phosphate salt and also as the free base and as tablets, elixir and solution for injection. • The 3-methoxy group protects the 3-position from glucuronide as occurs with morphine. • Codeine is used as an analgesic and antitussive. It is metabolized by cytochrome-mediated O-D to morphine (10% of dose), by cytochrome- mediated OND to norcodeine (11% activity of codeine), and conjugation to 6-O-glucuronide .

12. Esterification (acetylation) of both the 3- and 6-OH groups yields more lipophilic and more potent analgesic. Morphine Codeine Ethylmorphine (1) morphine R1 = Rz = H (2) codeine Rl = CH3, R2 = H (3) heroin Rl = Rz = COCH3 •Heroin was thus one of the first prodrugs.

13. • Esterification of the 6-OH enhanced lipophilicity of these compounds and their increased penetration in the CNS. Ring C Analogues

14. Modification in Alicyclic Ring= 7-8 unsaturation modification 15

15. N-Demethylation and realkylation yield N- allylnormorphine and nalorphine , which is a morphine antagonist .

16. • Annelation – adding a sixth ring across carbons 6 and 14 of the C ring of morphine – yields thebaine compounds such as etorphine which are extremely potent analgesics. These compounds as typically used to immobilize large animals (elephants). The Thebaines Thebaines

17. •Replacement of the N-methyl group of the thebaines with a methylcyclopropyl group yields compounds with mixed agonist/antagonist or partial agonist activity. •partial opiate agonist at m-receptors and an antagonist at k1 receptors Buprenorphine • Buprenorphine available as IM and sublingual administration has a half-life of about 5 hours. • It has moderate abuse potential. Because of its high affinity and slow dissociation from opiate receptors, larger doses of antagonists such as naloxone are required to produce reversal

18. Ring D Analogues and the Tertiary Amine Function • Replacement of morphine’s N-methyl group by a hydrogen atom as in normorphine reduces analgesic activity to 1/8th that of morphine. But substitution with aralkyl groups significantly increases analgesic activity.eg=N phenethylnormorphine

19. MORPHINE CLASSIFICATION BASED ON STRUCTURE

20. 1.MORPHINAN

21. 2. Benzomorphan Cylazocine Pentazocie

22. 3. 4-PHENYL PIPERDINES Meperidine

23. 4. 4-ANILIDOPIPERIDINES Sufentanil Alfentanil

24. 5. DIPHENYLHEPTANES METHADONE HYDROCHLORIDE equally potent to morphine or heroin; Highly addictive

25. 6. Miscellanious Drugs Tramadol Nalbuphine

26. Uses :- Analgesic  Hypnotic and sedative  Potent analgesic due to its central narcotic effect  CTZ stimulation in the medulla  Codeine is used as antitussive  Heroin is used as more narcotic and analgesic (habit forming drug)  Apomorphine has emetic action  Dihydromorphine –potent narcotic drug  Synthetic morphine compounds lilke opiods which are non habit forming but possess the medicinal activity of mophine