1. parasympathetic agents
Chapter 11
부교감신경계 약물
parasympathetic agents

2. Outline of Autonomic Nerve system

3. 교감 부교감 신경?

4. 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

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

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

7. Binding mode of Muscarinic-receptor

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

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

10. Binding mode of Muscarinic-receptor

11. Ach Receptor

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

14. Hydrolysis of Carbamate and Ester
Lower hydrolysis by Steric Hindrance of Alkyl Group
Lower the d+ effect by Electron donating Effect of N and Resonance(Tautomerization)

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

16. Cholinergic antagonist
Drug
Therapeutic use

17. Scopolamine nonprescription drug

18. Ginger for Motion sickness
Ginger is reported to calm the pyloric valve located at the base of the stomach. This relaxation of the valve allows the stomach to operate normally whereby the contents will enter the small intestine instead of being retained within the stomach. It is this undesirable effect of retention in the stomach that eventually results in vomiting.

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

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

21. The Life of Ach

22. Ach biosynthesis and hydrolysis

23. Acetylcholine Cl
Retrosynthesis

24. Synthesis I Synthesis II
Acetylcholine Cl
Synthesis I
Synthesis II

25. Bethanechol Chloride 2-Carbamoyloxypropyltrimethylammonium Chloride
Urecholine® (Odyssey), 하이네콜 정(일양)
임상용도 :수술후·분만후 기능성 요정체, 방광의 신경성 근이완증. 장관운동 촉진
저산증

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

27. Retrosynthesis 1
Retrosynthesis II

28. Bethanechol Chloride
Synthesis I

29. Bethanechol Chloride
Synthesis II

30. Neostigmine bromide
(3-Dimethylcarbamoyloxyphenyl)trimethylammonium Bromide
Prostigmin®
Acetylcholinesterase inhibitor (reversible)
임상적 용도: 1. 중증 근무력증 2. 비탈분극성 근이완제(투보쿠라린 등)의 해독제
3. 수술후ㆍ분만후 배뇨곤란.

31. Structural Similarity of Pyridostigmine to acetylcholine

32. Ach and AChE-I to Choline esterase
pyridostigmine

33. Retrosynthesis

34. Neostigmine bromide
Synthesis

35. Irreversible Inh. of Ach esterase

36. 2-PAM

37. Pilocarpine Bulky Group : Inhibit hydrolysis Binding to receptor
(3S,4R)-3-Ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one
Salagen® (Eisai), 살라겐 정(현대), 이솝토카핀 점안액
임상적 용도: 1. 두부암 또는 경부암에 대한 방사선요법에 의해 일어나는 타액선의
기능저하로 인한 구강건조증의 치료 2. 쇼그렌증후군 환자의 구강건조증 또는
안구건조증 치료. 점안액: 녹내장 진단 또는 치료를 목적으로 하는 축동 ...

39. Clinical Application of Pilocarpine
Pilocarpine has been used in the treatment of chronic open-angle glaucoma and acute angle-closure glaucoma for over 100 years. It acts on a subtype of muscarinic receptor (M3) found on the iris sphincter muscle, causing the muscle to contract and engage in miosis.
Pilocarpine also acts on the ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork through increased tension on the scleral spur. This action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure.
cf. Timolol(b-antagonist): Tomoptic(MSD)
In its ophthalmic form, it is used to treat open-angle and occasionally secondary glaucoma by reducing aqueous humour production through blockage of the beta receptors on the ciliary epithelium

40. Retrosynthesis ⇒ ⇒ ⇒

41. Pilocarpine
Synthesis A B

42. Mechanism of A

43. Mechanism of B

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

45. Retrosynthesis

46. Donepezil
Synthesis

47. Ach Antagonist

48. 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

49. Cholinergic antaginist and clinical application

50. 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), 아트로핀 주(대원) 오큐트로핀 점안액
임상적 용도: 농약등 신경 독성물질 해독
점안액: 가성근시 치료제, 안과진단 공공산대

51. Structural similarity of atropine to Ach

52. Structural characteristics of antagonist
Additional binding site
Propanetheline bromide

53. Retrosynthesis

54. Atropine sulfate
Synthesis
Tropine
O-acetyltropyl chloride
tropinone

55. Atropine sulfate
Synthesis of Tropine
decarboxylation

56. Synthesis of tropinone

57. Synthesis of Tropic acid
Atropine sulfate
Synthesis of Tropic acid

58. 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)
임상적 용도: 경련 및 운동기능 항진 : 위ㆍ십이지장궤양, 식도경련, 유문연축, 위염, 장염, 장산통, 경련성 변비, 기능성 설사, 담낭염, 담관염, 담석증, 담도이상

59. Butylscopolammonium Bromide
Synthesis

60. 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® 흡입액(Boehringer Ingelheim)
임상용도: 만성기관지염 등 폐쇄성 기도질환(COPD)의 치료에 사용되는 새로운 기전의 약물입니다. 기관지 수축의 원인이 되는 부교감 신경을 차단하여 기관지 확장 작용

61. Ipratropium Bromide
Synthesis

63. 전립선비대: 방광괄략근 이완-소변배출 억제-증상악화
녹내장: 안구 분비 억제-안압상승
전립선비대: 방광괄략근 이완-소변배출 억제-증상악화

65. 국소 작용 천식치료제 투여용기 흡입기의 종류(Inhaler) Inhaler의 방식
MDI(Metered Dose inhaler)
DPI(Dry Powder Inhaler)
Nebulizer
Inhaler의 방식
가압식: evohaler(GSK) aerosol
분말 흡입:turbuhaler, Diskus
흡입장치: Nebulizer

66. The benefit of inhalation treatment for asthma

67. The process for using Aerosol

69. Turbuhaler

70. Tropicamide
N-Ethyl-3-hydroxy-2-phenyl-N-(pyrid-4-yl methyl)propanamide
N-Ethyl-N-(r-picolyl)tropamide
미드리아실 점안액(알콘), 오큐트로픽 점안액(삼일)
임상적 용도:
주변부 망막까지 정확히 관찰하기 위해서 동공 산대

71. retrosynthesis

72. Ipratropium Bromide
Synthesis

73. Homatropine
8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-Hydroxy-2-phenylacetate Hydrobromide
1aH,5aH-Tropan-3a-yl Mandelate Hydrobromide
오큐 호마핀 점안액(삼일 알러간)
임상용도: 녹내장 등 수술후 동공 산대 목적, 포도막염 시에 치료하는 안약으로 수정체의 조절을 쉬게하며 동공이 확장되는 안약

74. Homatropine
Synthesis

75. Dicyclomine
(1,1’-Bicyclohexyl)-1-carboxylic acid 2-(Diethylamino)ethyl Ester
2-(Diethylamino)ethyl (Bicyclohexyl)-1-carboxylate
Bentylol® (Axcan), 디클로민 갑셀(영풍)
Acetylcholine 구조 유사체
임상적 용도: 위장운동조절 및 진경제입니다. 위십이지장궤양, 위염, 대장염, 담낭염, 게실염, 유문연축, 식도경련, 경련성 변비, 요로결석 등으로 인한 경련

78. Retrosynthesis

79. Dicyclomine
Synthesis

80. Cyclopentolate
2-Dimethylaminoethyl 2-(1-Hydroxycyclopentyl)-2-phenylacetate
-(1-Hydroxycyclopentyl)benzeneacetic acid 2-(Dimethylamino)ethyl Ester
Cycologyl® (Alcon) 점안액, 오큐시클로 점안액(삼일 앨러간)
Acetylcholine 구조 유사체 , 항 콜린작용
임상적 용도: 가성근시 치료용 산동제

81. retrosynthesis

82. Cyclopentolate
Synthesis

83. Oxybutynin
()-4-Diethylaminobut-2-ynyl-2-cyclohexyl 2-Hydroxy-2-phenylcetate
Ditropan® (동화, 맥네일, 얀센), 유로니틴(유영)
Acetylcholine 구조 유사체
임상적 용도:비억제성 반사신경성 방광에 기인한 불안정한 방광상태의 빈뇨, 절박뇨, 요실금, 다한증의 치료

86. Oxybutynin
Synthesis
methyl phenylcyclohexylglycolate

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

88. Propiverine 1-Methylpiperidin-4-yl 1,1-Diphenyl-1-propoxyacetate
Detrunorm® (Amdipharm), 베아베린(대웅), 유로스탑(국제), 비유피-4 정(제일)
임상적 용도: 빈뇨, 뇨실금: 신경인성 방광, 신경성 빈뇨, 불안정 방광, 방광자극상태(만성 방광염, 만성 전립선염)

91. Propiverine
Synthesis

92. Succinyl dichloride
2,2’-[(1,4-Dioxobutane-1,4-diyl)bis(oxy)]bis[N,N,N-trimethylethanaminium] Sulfate
Anectine® (Sandoz), 콜리신 주(명문)
Neuromuscular Blocking Agent
임상적 용도: 1. 마취시의 근이완 2. 기관내 삽관시 근이완유지 3. 골절탈구의 정복시 4. 후두경련의 근이완

94. Succinylcholine Chloride
Synthesis

95. 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), 아큐렉스(초당), 아크리움 주(명문)
Neuromuscular Blocking Agent

96. Synthesis
Atracurium besylate