Published on December 1, 2016
1. Structure activity relationship of opioids Dr.Ameya Puranik Junior Resident JNMC,Sawangi(M),Wardha.
2. Introduction • Natural opioids are opium or extracted from poppy straw. • Powdered opium contains number of alkaloids divided in two distinct groups 1) Phenanthrenes- Morphine,Codeine,Thebaine 2) Benzyllisoquinolines- Papaverine,Noscapine • Most of the semi-synthetic and synthetic derivatives are made by structural modifications of Morphine or Thebaine. • Morphine is considered as a prototype structure to study structural activity relationship of opioids.
3. Classification based on structure
4. Morphine(prototype) • Its is a primary alkaloid in opium family • Pentacyclic carbon ring structure • Only levorotatory isomer is active Its has six functional groups: • A tertiary nitrogen • Hydroxyl group attachment at (C3) • Hydroxyl group attachment at (C6) • Ether group • Double bond between C7-C8 • Hydrogen atom at (C14) • N-methyl is mainly responsible for analgesic effect
5. Morphine numbered structure
6. “Morphine rule” It is developed for generalization of structure activity relationship of various opioids, for the opioid to be active it should have atleast following characteristics in the structure: • A tertiary nitrogen atom. • A quarternary carbon,seperated from tertiary nitrogen by a bridge of two carbons. • Phenyl group attachment.
7. Phenolic hydroxyl group (C3) • It is needed for binding to Mu & Kappa receptors. • Seen in all potent Mu-agonists. • Changes at phenolic hydroxyl group: -OH -OCH3 (1/3) Decrease in activity(eg.Codeine)
8. Codeine • Naturally occurring opium • Replacement of –OCH3 at C3 • Also known as 3-methyl ether morphine. • --OCH3 causes weak Mu-agonist activity. • Analgesic activity reduced to 10%,but antitussive activity is retained. • --OH at C6 causes histamine release and allergic response if given parentally.
9. HEROIN • Acetylation of both the 3- and 6- OH produces 3,6- diacetylmorphine,also known as heroin. • This causes increased lipid solubility,which leads to enhanced and rapid CNS penetration. • Hence heroine is rapidly action and causes euphoric rush.
10. (C14)H/OH moiety • Addition of –OH group at 14 position causes: 1)Increase in activity by 2-3 times 2)Increases penetration of blood brain barrier 3)Decrease in anti-tussive action
11. 7,8 double bond
12. Hydroxy group at (C6) Modifications at C6: • Removal of –OH cause increase in lipophilicity. • Oxidation of hydroxyl group to ketone group eg. Hydromorphone and hydrocodone. • Acetylation of hydroxyl group eg. Heroin. • -OH group at C6 alone is associated with histamine release hence causes allergic response if given parentally eg.Codeine.
13. Hydromorphone Two structural changes: • Ketone bond at C6 • 7-8 double bond has been reduced to a single bond,by adding two hydrogen atoms(not shown) reduction of 7-8 + ketone at C6 Dihydro-morphine-one (dihydro) ( -one) • Both changes causes increase in activity by 6 times
14. Oxymorphone Three structural changes: • Ketone bond at C6 • 7-8 double bond has been reduced to a single bond,by adding two hydrogen atoms(not shown) • -H at C14 is replaced by –OH group • OXY-MORPH-ONE . The oxy refers to –OH on C14 -OH at C14 causes: • Increase in activity(2-3x),increase in BBB penetration. • Decrease in antitussive effect.
16. Ether linkage
17. Aromatic rings
18. N-Methyl group • Nitrogen group have major effects on pharmacological activity of opioid • Narcotic anatagonists are made by using oxymorphone structure with modified substituents on the nitrogen The Nitrogen is mostly tertiary with a methyl substitution in morphine. The size of substituent on Nitrogen dictates potency and agonist or antagonist activity. a) Increasing size from methyl (i.e. 1 C) to 3 or 5 carbon (especially with double bonds or small cyclic/aromatic rings) results in antagonist activity b) Further larger substitution restores agonist activity in more potent form(eg.Etorphine LD50 is 30mcg)
19. Thank you