parasympathetic agents Chapter 11 부교감신경계 약물 parasympathetic agents

Outline of autonomic Nerve system

교감 부교감 신경?

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

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

Binding mode of Muscarinic-receptor

Binding mode of Ach at Nicotinic receptor Acetyl choline Nicotine

How can Ach open the Channel (Conformational Change)

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

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

Drug Therapeutic use

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

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

The Life of Ach

Ach biosynthesis and hydrolysis

Acetylcholine Cl Retrosynthesis

Synthesis I Synthesis II Acetylcholine Cl Synthesis I Synthesis II

Bethanechol Chloride 2-Carbamoyloxypropyltrimethylammonium Chloride Urecholine® (Odyssey)

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

Retrosynthesis 1 Retrosynthesis II

Bethanechol Chloride Synthesis I

Bethanechol Chloride Synthesis II

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

Structural Similarity of Pyridostigmine to acetylcholine

Ach and AChE-I to Choline esterase pyridostigmine

Retrosynthesis

Neostigmine bromide Synthesis

Irreversible Inh. of Ach esterase

2-PAM

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

Retrosynthesis ⇒ ⇒ ⇒

Pilocarpine Synthesis

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

Retrosynthesis

Donepezil Synthesis

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

Ach Antagonist

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)

Structural similarity of atropine to Ach

Structural characteristics of antagonist Additional binding site

Atropine sulfate Synthesis Tropine O-acetyltropyl chloride

Atropine sulfate Synthesis of Tropine decarboxylation

Synthesis of Tropic acid Atropine sulfate

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[3.3.1.02,4]nonane Bromide Buscopan® (Boeringer-Ingelheim)

Butylscopolammonium Bromide Synthesis

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)

Ipratropium Bromide Synthesis

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)

Ipratropium Bromide Synthesis

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

Homatropine Synthesis

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

Dicyclomine Synthesis

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

Synthesis Cyclopentolate

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

Synthesis Oxybutynin methyl phenylcyclohexylglycolate

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

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

Synthesis Propiverine

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

Succinylcholine Chloride Synthesis Succinylcholine Chloride

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

Synthesis Atracurium besylate