1. parasympathetic agents
Chapter 11
부교감신경계 약물
parasympathetic agents

2. Outline of autonomic Nerve system

3. 교감 부교감 신경?

4. Ach Receptor muscarine Acetyl choline nicotine Muscarinic receptor
Location:
heart, smooth muscle, brain, exocrine gland
Types:
M1: gastric perietal cell
M2: cardiac cell
M3: exocrine gland and smooth muscle
Nicotinic Receptor
Location:
CNS, adrenal medular, skeletal muscle, autonomic ganglia neuro muscular junction
Nicotinic receptor

5. Ach action and clinical application
- Decrease in heart rate and cardiac out put
- vasodilation
Increase motility
- stimulate secretion (bronchiole ,salivation)
- Stimulate detrusor muscle(explusion of urine)
위무력, 저산증
상복부 팽만
배뇨장애
- stimulate secretion of sweat
Ciliary muscle contraction
constriction of pupil
녹내장

6. Binding mode of Muscarinic-receptor

7. Binding mode of Ach at Nicotinic receptor
Acetyl choline
Nicotine

8. How can Ach open the Channel (Conformational Change)

9. Conformation of Ach
Active at N-receptor
Active at M-receptor

10. Cholinergic drug and application
녹내장,
근무력증
배뇨장애
위무력, 저산증
녹내장,
안과수술시 안압강하
농약중독
배뇨장애
위무력, 녹내장
근무력증

11. Drug
Therapeutic use

12. Side effect of choline related Drug
Cholinergic drug
Choline antagonist
Side effect of choline related Drug

13. Acetylcholine Chloride
2-Acetyloxy-N,N,N-trimethylethanaminium Chloride
마이오콜-주 ®(Novartis)

14. The Life of Ach

15. Ach biosynthesis and hydrolysis

16. Acetylcholine Cl
Retrosynthesis

17. Synthesis I Synthesis II
Acetylcholine Cl
Synthesis I
Synthesis II

18. Bethanechol Chloride 2-Carbamoyloxypropyltrimethylammonium Chloride
Urecholine® (Odyssey)

19. Ach Derivatives Introduction of alkyl chain to inhibit hydroysis
Conversion of ester to other functinal group to stablize in hydrolysis

20. Retrosynthesis 1
Retrosynthesis II

21. Bethanechol Chloride
Synthesis I

22. Bethanechol Chloride
Synthesis II

23. Neostigmine bromide
(3-Dimethylcarbamoyloxyphenyl)trimethylammonium Bromide
Prostigmin®
Acetylcholinesterase inhibitor (reversible)

24. Structural Similarity of Pyridostigmine to acetylcholine

25. Ach and AChE-I to Choline esterase
pyridostigmine

26. Retrosynthesis

27. Neostigmine bromide
Synthesis

28. Irreversible Inh. of Ach esterase

29. 2-PAM

30. Philocarpine
(3S,4R)-3-Ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one
Salagen® (Eisai), 살라겐 정(현대)

31. Retrosynthesis ⇒ ⇒ ⇒

32. Pilocarpine
Synthesis

35. Donepezil
5,6-Dimethoxy-2-[[1-(phenylmethyl)piperidin-4-yl]methyl]-2,3-dihydroinden-1-one
Aricept® (Eisai/Pfizer)

36. Retrosynthesis

37. Donepezil
Synthesis

38. Ach Antagonist Tropic Acid계 약물 Atropine Sulfate
Butylscopolammonium Bromide
Ipratropium Bromide
Tropamide
Homatropine Hydrobromide
Acetylcholine 구조 유사체 약물
Dicyclomine
Cyclopentolate
Oxybutynin
Propiverine
니코틴성 길항제 (Neuromuscular Blocking Agent)
Succinylcholine Chloride
Atracurium Besylate

39. Ach Antagonist

40. Atropine sulfate
endo-a-(Hydroxymethyl)benzeneacetic Acid 8-Methyl-8-azabicyclo[3.2.1]octt-3-yl Ester
8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-Hydroxy-2-phenylpropanoate
1aH,5aH-Tropan-3a-ol Tropate
Atrophen® (Meridian Medical Tech)

41. Structural similarity of atropine to Ach

42. Structural characteristics of antagonist
Additional binding site

43. Atropine sulfate
Synthesis
Tropine
O-acetyltropyl chloride

44. Atropine sulfate
Synthesis of Tropine
decarboxylation

45. Synthesis of Tropic acid
Atropine sulfate

46. Butylscopolammonium bromide
N-Butylscopolammonium Bromide
[7(S)-(1a,2b,5a,7b)]-9-Butyl-7-(3-hydroxy-1-oxo-2-phenylpropoxy)-9-methyl-3-oxa-9-azoniatricyclo[ ,4]nonane Bromide
Buscopan® (Boeringer-Ingelheim)

47. Butylscopolammonium Bromide
Synthesis

48. Ipratropium Bromide Isopropylnoratropine Methobromide
[(1R,5R)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl]-3-hydroxy-2-phenylpropanoate
Atrovent® (Boehringer Ingelheim)

49. Ipratropium Bromide
Synthesis

50. Tropamide Isopropylnoratropine Methobromide
[(1R,5R)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl]-3-hydroxy-2-phenylpropanoate
Atrovent® (Boehringer Ingelheim)

51. Ipratropium Bromide
Synthesis

52. Homatropine
8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-Hydroxy-2-phenylacetate Hydrobromide
1aH,5aH-Tropan-3a-yl Mandelate Hydrobromide

53. Homatropine
Synthesis

54. Dicyclomine
(1,1’-Bicyclohexyl)-1-carboxylic acid 2-(Diethylamino)ethyl Ester
2-(Diethylamino)ethyl (Bicyclohexyl)-1-carboxylate
Bentylol® (Axcan)
Acetylcholine 구조 유사체

55. Dicyclomine
Synthesis

56. Cyclopentolate
2-Dimethylaminoethyl 2-(1-Hydroxycyclopentyl)-2-phenylacetate
-(1-Hydroxycyclopentyl)benzeneacetic acid 2-(Dimethylamino)ethyl Ester
Cycologyl® (Alcon)
Acetylcholine 구조 유사체

57. Synthesis
Cyclopentolate

58. Oxybutynin
()-4-Diethylaminobut-2-ynyl-2-cyclohexyl 2-Hydroxy-2-phenylcetate
Ditropan® (Ortho McNeil Janssen)
Acetylcholine 구조 유사체

59. Synthesis
Oxybutynin
methyl phenylcyclohexylglycolate

60. Synthesis of (S)-phenylcyclohexylglycolic acid (1)
Oxybutynin
Synthesis of (S)-phenylcyclohexylglycolic acid (1)

61. Propiverine 1-Methylpiperidin-4-yl 1,1-Diphenyl-1-propoxyacetate
Detrunorm® (Amdipharm)

62. Synthesis
Propiverine

63. Succinyl dichloride
2,2’-[(1,4-Dioxobutane-1,4-diyl)bis(oxy)]bis[N,N,N-trimethylethanaminium] Sulfate
Anectine® (Sandoz)
Neuromuscular Blocking Agent

64. Succinylcholine Chloride
Synthesis
Succinylcholine Chloride

65. Atracurium Bestylate
5-[3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoyloxy]pentyl 3-[1-[(3,4-Dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoate
Nimbex® (Abbott)
Neuromuscular Blocking Agent

66. Synthesis
Atracurium besylate