SAR of Morphine

This is a ppt on QSAR- Hammett and Hansch plot in drug design and morphine was used as an example.

1. HAMMETT AND HANSCH PLOT IN DRUG FORMULATION Presented by Naraino Majie Nabiilah and Joorawon Svenia Date: 10 th November 2014

2. Table of Content Introduction Modification of lead compound Drug design a) Lipophilicity b) Electronic effects (Hammett plot) c) Steric effects d) Hansch analysis Morphine as example Conclusion References

3. INTRODUCTION

4. INTRODUCTION SAR is an advance designed to find the relationships between chemical structure and biological activity of studied compounds. Therefore it is the concept of linking chemical structure to a chemical property or biological activity including toxicity. The theory of SARs is to produce new drugs with similar structure and effects as the original one but with having more potency and improved side-effects. Moreover, SARs are essential for toxicological studies on a compound. SARs have been used since long ago to design chemicals with the commercially wanted properties and thus they are important while designing drugs as the chemicals with desired pharmacological and therapeutic activities are known.

5. There are various factors that should be considered while developing the mechanism of SARs, these are: the size and shape of the carbon skeleton, the nature and degree of substitution and the stereochemistry. During modifications on a drug analogue, effects on water solubility, transport through membranes, receptor binding, metabolism and other pharmacokinetics properties should be considered. Computer assisted molecular modelling helps to solve this problem by providing accurate targeting. INTRODUCTION

6. MODIFICATION OF LEAD

7. Varying size and shape Changing the number of methylene groups in chains and rings This increases lipophilicity which results in an increased in activity Water solubility is reduced as well as activity No selective binding due to micelle formation in aliphatic compounds Increasing or decreasing the degree of unsaturation A change in the degree of unsaturation causes an increase in rigidity, complication of E-Z isomers, more sensitivity and increased toxicity. Introducing or removing a ring system This results to an increase in size, shape changes and stability of structure with the substitution of C=C double bonds. MODIFICATION OF LEAD

8. Introduction of new substituents New substituents may occupy the same position as the previous compound but each will have its own characteristics, pharmacokinetic and pharmacodynamics properties to the analogue. Methyl group Halogen group Hydroxy group Amino group Carboxylic group Sulphonic group MODIFICATION OF LEAD

9. Bioisosterism Substituents or groups with chemical and physical properties. Can attenuate toxicity, modify activity of a lead and Alter the pharmacokinetics profile of the lead. There are two types of bioisosterism : Classical isosteres - have same number of atoms and fit the steric and electronic rules and have similar biological activity Non- Classical isosteres - do not have same number of atoms and do not fit the steric and electronic rules but have similar biological activity MODIFICATION OF LEAD

10. DRUG DESIGN

11. SAR general equation is: Biological activity = function {parameter(s)} The following should be considered for drug design a) Lipophilicity Partition coefficient (P) and lipophilicity substituent constant (π) are the two parameters that represent lipophilicity. DRUG DESIGN

12. DRUG DESIGN

13. b) Electronic effects The activity of a drug is also affected by the distribution of electrons in the molecule. Drugs in unionised form are carried easier through the membranes compared to drugs in ionised form. The Hammett constant is used to quantify the electronic effects.   DRUG DESIGN

14. c) Steric effects   DRUG DESIGN

15. d) Hansch analysis  It tries to relate drug activity to measurable chemical properties. According to Hansch, drug action is divided into 2 stages: Transport of drug to its site of action Binding of drug to target site Each stage depends on chemical and physical properties of drug and target site. Hansch suggested that biological activity of drug is related to parameters by the mathematical equation: DRUG DESIGN

16. The accuracy of the above equation depends on: The number of analogues (n) used; greater n  more accurate The accuracy of biological data used in the derivation of equation Choice of parameter Accuracy also depends on values of standard deviation and regression constant. Hansch analysis is used to indicate the importance of a parameter on a mechanism by which a drug acts. DRUG DESIGN

17. CRAIG PLOTS Helps in determining suitable susbtituents to quickly decide which analogs to synthesize. Plots of one parameter against another. For example, p vs. s Once the Hansch equation has been derived, it will show whether p or s should be negative or positive in order to get good biological activity .

18. MORPHINE

19. MORPHINE Morphine, C 17 H 19 NO 3 , is the most abundant of opium’s 24 alkaloids, accounting for 9 to 14% of opium-extract by mass. Named after the Roman god of dreams, Morpheus, who also became the god of slumber, the drug morphine numbs pain, alters mood and induces sleep. Less popular and less mentioned effects include nausea, vomiting and decreased gastrointestinal motility. The three dimensional structure of morphine is fascinating. It consists of five rings, three of which are approximately in the same plane. The other two rings, including the nitrogen one, are each at right angles to the other trio. 

20. 1923 MORPHINE O NMe HO HO Structure

21. MORPHINE O NMe HO HO 1923 Structure

22. MORPHINE O NMe HO HO 1923 Structure

23. Structure

24. Structure

25. Structure

26. Structure

27. T-Shaped molecule Structure Log P: 0.89

28. Potential Binding Groups Functional groups Carbon skeleton

29. Phenol Ether Alcohol Amine O NMe HO HO Potential Binding Groups

30. Phenol Ether Alcohol Aromatic ring Alkene Amine O NMe HO HO Potential Binding Groups

31. Structure Activity Relationships Mask or remove a functional group Test the analogue for activity Determines the importance or other wise of a functional group for activity

32. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO HO

33. O NMe HO STRUCTURE ACTIVITY RELATIONSHIPS

34. O NMe HO HO STRUCTURE ACTIVITY RELATIONSHIPS

35. O NMe HO STRUCTURE ACTIVITY RELATIONSHIPS

36. O NMe HO HO STRUCTURE ACTIVITY RELATIONSHIPS

37. SAR - The phenol moiety R=H Morphine R=Me Codeine Codeine 20% active (injected peripherally) 0.1% active (injected into brain) N Me O R O H O H H Log P: 1.19

38. SAR - The phenol moiety Notes 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. Conclusion Masking phenol is bad for activity

39. SAR - The phenol moiety R=Ac 3-Acetylmorphine Decreased activity Acetyl masks the polar phenol group Compound crosses the blood brain barrier more easily Acetyl group is hydrolysed in the brain to form morphine N Me O R O H O H H

40. SAR - The 6-alcohol R=Me Heterocodeine 5 x activity N Me O H O R O H H

41. SAR - The 6-alcohol Activity increases due to reduced polarity Compounds cross the blood brain barrier more easily 6-OH is not important for binding N Me O H O H O N Me O H O O N Me O H O Log P: 2.50 Log P: 0.89 Morphine Hydromorphone Log P: 0.90 Desomorphine

42. SAR - The 6-alcohol R=Ac 6-Acetylmorphine Increased activity (4x) Acetyl masks a polar alcohol group making it easier to cross BBB Phenol group is free and molecule can bind immediately Dependence is very high 6-Acetylmorphine is banned in many countries N Me O H O R O H H Log P: 1.55

43. SAR - The 6-alcohol and phenol R=Ac Heroin Increased activity (2x ) Increased lipid solubility Heroin crosses the blood brain barrier more quickly Acetyl groups are hydrolysed in the brain to generate morphine Fast onset and intense euphoric effects N Me O R O R O H H Log P: 1.58

44. SAR - Double bond at 7,8 Dihydromorphine Increased activity The alkene group is not important to binding N Me O H O H O H H Log P: 1.26

45. SAR - Nitrogen No activity Nitrogen is essential to binding CHMe O H O H O H H

46. SAR - Methyl group on nitrogen NR= NH Normorphine Reduced activity (25%) Normorphine is more polar and crosses the BBB slowly Ionized molecules cannot cross the BBB and are inactive Ionized structures are active if injected directly into brain R affects whether the analogue is an agonist or an antagonist No activity NR= N + Me 2 No activity N R O H O H O H H O NR= NMe + - Log P: -1.56 N-Oxide Quaternary salt

47. SAR - Stereochemistry Mirror image of morphine No activity 10% activity Changing the stereochemistry is detrimental to activity N R O H O H O H H N R O H O H O H H

48. HBD or HBA Ionic (N is protonated ) van der Waals SAR - Important binding interactions N Me O HO H O H H

49. CONCLUSION

50. CONCLUSION Medicinal chemistry has and will continue to play an important role in today's society as it deals with development, synthesis and design of pharmaceutical drugs. These results are then used to give us a better understanding of diseases as well as giving us ways of preventing and curing them. Although medicinal chemistry is about creating new drugs, the properties and quantitative structure activity relationships (QSAR) of existing drugs is important to see if a combination of these biological properties can be mixed with a new hit to produce the latest drug that will help fight against various diseases.

51. CONCLUSION As the majority of medicinal chemistry is based around the discovery of new drugs and development many companies spend a considerable amount of money and maintaining and improving their database of information to ensure that each test is run as efficient as possible. Of course, thousands of compounds related to the morphine structure have been prepared and many without activity, and no compound has been found to halt the terrible addictive morphine properties. Used correctly, the morphine family is an important class of analgesics, and their study represents an important contribution to the understanding of medicinal activity.

52. REFERENCES ANON, 2014. Assessment of chemicals. Introduction to (Quantitative) structure activity relationships [online]. Available from: http://www.oecd.org/chemicalsafety/risk-assessment/introductiontoquantitativestructureactivityrelationships.htm MCKINNEY, J.D. et al, 2000. Toxicological sciences. The practice of structure activity relationships (SAR) in toxicology [online], 56(1), 8-17. Available from: http://toxsci.oxfordjournals.org/content/56/1/8.full PARIKH, 2009. Medicinal Chemistry. The SAR & QSAR approaches to drug design [online]. Available from: http://faculty.mville.edu/parikhs/courses/chm2004/lecture%20notes/CHM%202004%20Lectures%20-%20Chapter%204.pdf TOROK, B. Medicinal chemistry. SAR and QSAR [online]. Available from: http://alpha.chem.umb.edu/chemistry/ch458/files/Lecture_Slides/Lecture_Chapter_3.pdf [Accessed on 8 November 2014]. MANIBUSAN, M. et al, 2012. Technical working group on pesticides. (Quantitative) structure activity relationship [(Q)SAR] guidance document [online]. Available from: http://www.epa.gov/oppfead1/international/naftatwg/guidance/qsar-guidance.pdf

53. REFERENCES ANON, 2014. Wikipedia. Louis Plack Hammett [online]. Available from: http://en.wikipedia.org/wiki/Louis_Plack_Hammett ANON, 2014. Wikipedia. Corwin Hansch [online]. Available from: http://en.wikipedia.org/wiki/Corwin_Hansch Medicinal Chemistry- Chapter 3, QSAR of Morphine. Available at: http://carbon.indstate.edu/rfitch/CHEM%20452/Chapter_3.pdf Anon, Morphine Chemistry, Online. Available at: http://www.emsb.qc.ca/laurenhill/science/morphine.html Anon, 2012, A Look at the Morphinan Structure Activity Relationships of Six Popular Opiates, Online. Available at: http://opiophilia.blogspot.com/2012/12/opiate-structure-activity-relationship.html Florencio Zaragoza Dörwald : Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds

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