Anticholinergics Med Chem Lecture

Med chem lecture on Anticholinergic drugs for B.Pharm level in Nepal
Content from Foye's Principle of medicinal chemistry, my own thoughts and some articles

1. Anticholinergics Acetylcholine (Ach) Drugs that directly inhibit pharmacological response of Ach

2. Muscarine antagonist/ antispamodics These drugs block the response of Ach in the muscarine receptor by competitively binding to it and inhibiting any response. They have opposite pharmacological response of Ach ie if Ach agonist slows heart rate then Ach antagonist speeds heart rate or if Ach relaxes bladder then it antagonist constricts it

3. Their medical use is in in Sooth muscle spasm in cold n flu (to reduce nasal secretion) previously in ulcer (but now replaced by H2 antagonist and proton inhibitors) Overactive bladder (to much urination) Motion sickness Treat organophosphate poisoning (still doesn’t work in aging and doesn’t treat respiratory failure) Parkinson (brain disease where nerves start degrading and person slowly goes crazy)

4. SAR of anticholinergics Atropine was the first drug of this type and was used to generate SAR. It was noted that unlike Ach, the terminal ester carbon in Atropine had a bulky substituent . This was considered important and modifications were done there

5. 1) The R1 or R2 groups must be carbocyclic or heterocyclic, but if both are cyclic it gives maximal antagonist potency. The rings may be same or different. One of is generally aromatic and other is saturated ring or olefinic group ( ie it has a C-C double bond) Rings may be same or different The benzene could be any type Cyclohexane (non-aromatic carbocyclic or pyridine (aromatic heterocyclic) or Pyrrolidine (non-aromatic heterocyclic General framework of Anticholinergics

6. Detect R1-R3 and X

7. 2)The R3 group can be hydrogen, hydroxyl (-OH) , hydroxymethyl (-CH2OH), amide ( ) or a component of the R1 and R2 group . Best potency is seen with hydroxyl or hydroxymethyl ( this hints that the oxygen group must be participating in H bond) Hydrogen Hydroxyl Hydroxymethyl Amide Component of R2 and R3

8. 3) The X is mostly ester in most potent derivatives but it can be a ether oxygen or absent completely Mostly ester Or else ether Or absent completely

9. 4) The N substituent cab be both quaternary ammonium salt or tertiary amine with different alkyl groups. Most potent derivatives have quaternary ammonium salt. The alkyl group is not restricted to only methyl (as in SAR of Ach agonist). It can be ethyl, propyl or isopropyl. Quaternary form is most potent Alkyl = methyl Alkyl = ethyl Alkyl = isopropyl

10. 5) The distance between the ring substituted carbon and nitrogen is not fixed ie it can vary The no. of alkyl units between that carbon and nitrogen can vary from 2-4, with most potency in case of two CH2 units.(this is also unlike SAR of Ach agonist where the CH2 units should not be more than 2). 2 CH2 units is best distance 2 CH2 units (don’t count O or N, just C) 3 CH2 (don’t count double or triple bonded carbon. Only count single carbons)

11. summary The R1 or R2 groups must be carbocyclic or heterocyclic The R3 group can be hydrogen, hydroxyl (-OH), hydroxymethyl (-CH2OH), amide or a component of the R2 and R3 group The X is mostly ester in most potent derivatives but it can be a ether oxygen or absent completely The N substituent cab be both quaternary ammonium salt or tertiary amine with different alkyl groups The distance between the ring substituted carbon and nitrogen is not fixed but maximum potency requires about 2 carbon units (Note: The SAR does not say anything about selectivity for muscarinic subtypes)

12. What happens during muscular spam? A muscle spasm, or muscle cramp, is an involuntary contraction of a muscle . Muscle spasms occur suddenly, usually resolve quickly, and are often painful. Both skeletal muscle and smooth muscle are effected by it. Spasms may occur when a muscle is overused and tired, particularly if it is overstretched or if it has been held in the same position for a prolonged period of time. The muscle becomes hyperexcitable , resulting in a forceful contraction

13. Contrast between SAR of Ach agonist and antagonist A) Nitrogen group In agonist the N can only be quanternary but In antagonist N can be both quanternary or tertiary Methacholone

14. B) Ethylene group In agonist the no of ethylene is fixed at only 2 but In antagonist no of ethylene can range from 2-4 Bethanecol carbamate

15. C) Selectivity In agonist the methyl substitution in ethylene group controls selectivity of muscarinic or nicotinic but In antagonist no such feature is present . Still It only antagonizes muscarinic only Methacholone Muscarinic selective

16. D) Ester group or X group In agonist ester is not needed and can be removed but an Oxygen must exist in it’s place In antagonist ester is not needed and can be removed but an Oxygen need not exist in it’s place

17. Mostly ester Oxygen in place on ether Oxygen absent Ester Ether Ketone

18. E) Rule of five and terminal carbon In agonist rule of five is followed and terminal carbon is bonded to Hydrogens In antagonist, rule of five is not followed and the terminal carbon is bonded to two bulky ring groups Methacholone

19. Spot the associated functional groups

20. Specific Muscarinic antagonists Aminoalcohol esters Atropine Scopolamine Aminoamide Tropicamide Aminoether Benztropine Orphenadrine Micellneous Solifenacin Darifenacin While all of these are selective to muscarinic receptor they are not selective to a specfic subtype eg M1, or M2 etc. Only the last two Solifenacin and Darifenacin show selectivity to M3.

21. Atropine Scopolamine Dicyclomine Tropicamide

22. Atropine It is anticholinergic that blocks muscarinic receptors It is an alkaloid extracted from Solanaceae plant and was the first anticholinergic . It is an ester of tropine and tropic acid and used as a sulphate Salt in racemic from At therapeutic does it can penetrate the brain and stimulate the CNS Uses Treat Bardycardia Reduce secretion before surgery Treat Iritis (painful inflammation of eye) Organophosphate poisoning (only to decrease muscarinic action, not an antidote like PAM) MOA – It competitively binds to muscarinic receptor and antagonizes it thus blocking all cholinergic effects

23. Atropine synthesis

24. Scopolamine It is anticholinergic that blocks muscarinic receptors It is an alkaloid extracted from Solanaceae plant It is used as salt hydrobromide salt in enantiopure (-) form At therapeutic does it depresses CNS Uses Treat Iritis (painful inflammation of eye) Treat Parkinson Treat Motion sickness MOA - It competitively binds to muscarinic receptor and antagonizes it thus blocking all cholinergic effects

25. Dicyclomine It is an anticholinergic that blocks muscarinic receptors It is a weaker antagonist than atropine and doesn’t stimulate the brain Uses treat intestinal hypermotility (causes constipation and diarrhea and decreased opportunity for the absorption of nutrients) irritable bowel syndrome (a disorder in large intestine that causes cramping, abdominal pain, bloating, gas) MOA - It competitively binds to muscarinic receptor and antagonizes it thus blocking all cholinergic effects

26. Synthesis

27. Tropicamide It is an anticholinergic that blocks muscarinic receptors Its duration of action is shorter than Atropine Uses Mydriatic (drug that dilates pupil) Cycloplegia (to fix eye movement) MOA - It competitively binds to muscarinic receptor and antagonizes it thus blocking all cholinergic effects

28. Synthesis

29. Newer Muscarinic Antagonist Newer drugs focus on subtype selectivity and don’t have defined SAR Older SAR based non-selective drug Selective to M1 Selective to M2 Observe the use of tri-cyclic ring and how minor modification changed Selectivity from M1 to M2. This is true not just here in in every case

30. Acetylcholine and muscle contraction

31. Ach binds to it’s receptor in muscle Myosin cross-bridges with Actin leading to contraction Action potential (AP)is generated AP causes Release of Ca2+ from SR Muscle return back to relaxed state AP ends and Ca2+ is put back into SR Events during Muscle contraction

32. Events during an action potential An action potential is a temporary “all or nothing” changes in cell membrane potential. During this period cell is taken from polarized to depolarized state Depolarizing blockers keep maintaining depolarized state

33. Nicotinic antagonist Nicotinic Antagonist competitively bind to nicotinic receptors and block nicotinic response which results in blockade of skeletal muscle contraction ie paralysis There are two types Neuromuscular Blockers (not the same as skeletal muscle relaxant that work by CNS depression) Ganglionic Blockers (We will only discuss the first)

34. Neuromuscular Blockers The first Neuromuscular Blockers was extracted from the plant cucare which contained Tubocuraine . It was noted that given in normal condition, they cause muscle paralysis. Tribesmen of Amazon used it in their arrows for hunting. The poison will cause respiratory failure in the prey

35. Therapeutic application As an Adjunct to general Anesthetic ,(general Anesthetic are drugs that makes you unconscious for surgery) they lower the dose of Anesthetic thus lowering side effects and promoting postanesthetic recovery time and Tracheal intubation (putting tube inside food pipe) or endoscopy (putting tube inside rectum) Correct bone dislocation 2 types Non-depolarizing (desired property) Depolarizing (undesired property)

36. SAR Two quaternary ammonium salts separated by 10-12 carbon units is the only known general requirement. This follows from the observation that nicotinic receptor has two cationic site

37. Succinylcholine Chloride It is a depolarizing neuromuscular blocker. This depolarization effect makes the muscle fiber resistant to further stimulation by Ach. This nature makes it therapeutically undesirable in comparison to the Non-depolarizing blockers It is a dimer (two same molecules joining each other) of acetylcholine molecules Like Ach, it’s is rapidly metabolized in blood and thus has short duration of action of about 6 to 8 mins Uses Endotracheal insertions Endoscopy MOA – It antagonizes nicotinic receptors at neuromuscular junction which causes skeletal muscle paralysis

38. Think of modification to improve duration of action of Succinylcholine Chloride Hint- Rapid metabolism is due to hydrolysis of ester

39. synthesis

40. D- Tubocuraine It is a Non-depolarizing neuromuscular blocker. It doesn’t make the muscle fiber resistant to further stimulation by Ach. This nature makes it therapeutically desirable in comparison to the depolarizing blockers It is metabolically stable , only 1 % is degraded by liver, thus acts for a longer period of about 80-120 mins It’s preparation includes bisulfites (an anti-oxidant) which causes histamine release thus can cause allergic reactions Uses MOA – It antagonizes nicotinic receptors at neuromuscular junction which causes skeletal muscle paralysis

41. Point to be noted Being metabolically allows drug to be active for longer periods but it also means that the only way to get rid of their effect is excretion through the kidney. Thus in patients with kidney failure, such characteristic can cause trouble. An ideal drug must be readily expelled from body. In such case does might need to be lowered.

42. Thank You

43. Drugs from Plants and HTS Drug Plant Class Chemical Type Atropine Solanaceae Antimuscarinic Alkaloid Tubocuraine Curare Antinicotinic Alkaloid Physostigmine calabar beans Reversible AChE inhibtor Alkaloid Historically, Plants have always been the source of the first drugs in a class. Both Atropine and Tubocuraine were the first of their kind and notice they were all alkaloids, along with Physostigmine . The only downside to this process is that there are thousands of plants and each plant typically contain a multitude of compounds, that testing for each and every one against a receptor/enzyme is a very exhaustive process. Thankfully, the industry can test thousands of compounds in few days using High Throughput Screening(HTS) which are automatic and robotic system. To use it first we have to design as assay. This is now available in academia too.

44. In these systems drugs/compounds are injected into plates that contain many hole which actually is a individual assay that contains receptor/enzyme on which we desire to find if the drug has any activity or not In each hole different drug concentration is injected Successful drugs generally gives some kind of visible color change (colorimetric assay) or change in fluroscence reading ( florimetric assay) in every hole in the plate. All the data for every hole can be seen easily in a computer screen The intensity of color change and fluroscence reading allows to both qualify and quantify drug action at that concentration If a compound is having good activity, medicinal chemists alter it to improve potency/selectivity

45. HTS machine looks like this For more info: Watch this video https://www.youtube.com/watch?v=EQC5MViYCtI Read : http://ajpcell.physiology.org/content/286/3/C465