parasympathetic agents Chapter 11 부교감신경계 약물 parasympathetic agents

Outline of Autonomic Nerve system

교감 부교감 신경?

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

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

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

Binding mode of Muscarinic-receptor

Binding mode of Ach at Nicotinic receptor Acetyl choline Nicotine

How can Ach open the Channel (Conformational Change)

Binding mode of Muscarinic-receptor

Ach Receptor

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

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)

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

Cholinergic antagonist Drug Therapeutic use

Scopolamine nonprescription drug

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.

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), 하이네콜 정(일양) 임상용도 :수술후·분만후 기능성 요정체, 방광의 신경성 근이완증. 장관운동 촉진 저산증

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) 임상적 용도: 1. 중증 근무력증 2. 비탈분극성 근이완제(투보쿠라린 등)의 해독제 3. 수술후ㆍ분만후 배뇨곤란.

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

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 ...

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

Retrosynthesis ⇒ ⇒ ⇒

Pilocarpine Synthesis A B

Mechanism of A

Mechanism of B

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

Retrosynthesis

Donepezil Synthesis

Ach Antagonist

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

Cholinergic antaginist and clinical application

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

Structural similarity of atropine to Ach

Structural characteristics of antagonist Additional binding site Propanetheline bromide

Retrosynthesis

Atropine sulfate Synthesis Tropine O-acetyltropyl chloride tropinone

Atropine sulfate Synthesis of Tropine decarboxylation

Synthesis of tropinone

Synthesis of Tropic acid Atropine sulfate Synthesis of Tropic acid

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

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® 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

Ipratropium Bromide Synthesis

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

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

The benefit of inhalation treatment for asthma

The process for using Aerosol

Turbuhaler

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

retrosynthesis

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 오큐 호마핀 점안액(삼일 알러간) 임상용도: 녹내장 등 수술후 동공 산대 목적, 포도막염 시에 치료하는 안약으로 수정체의 조절을 쉬게하며 동공이 확장되는 안약

Homatropine Synthesis

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

Retrosynthesis

Dicyclomine Synthesis

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

retrosynthesis

Cyclopentolate Synthesis

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

Oxybutynin Synthesis 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), 베아베린(대웅), 유로스탑(국제), 비유피-4 정(제일) 임상적 용도: 빈뇨, 뇨실금: 신경인성 방광, 신경성 빈뇨, 불안정 방광, 방광자극상태(만성 방광염, 만성 전립선염)

Propiverine Synthesis

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

Succinylcholine Chloride Synthesis

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

Synthesis Atracurium besylate