山东大学：《药物化学 Medicinal Chemistry》课程教学资源（PPT课件讲稿）Chapter 03 外周神经系统药物 Peripheral nervous system drugs

Medicinal Chemistry Chapter 3 Peripheral Nervous System Drugs

Medicinal Chemistry Chapter 3 Peripheral Nervous System Drugs

Outline Drug Affecting Cholinergic Cholinergic Drugs Neurotransmission Anticholinergic drugs Drug Affecting Adrenergic+ Adrenergic Drugs(agonist Neurotransmission Adrenergic Antagonist (Chapter 4) Antihistamines Histamine H, Receptor Antagonists Local Anesthetics

Outline Drug Affecting Cholinergic Neurotransmission Cholinergic Drugs Anticholinergic Drugs Drug Affecting Adrenergic Neurotransmission Adrenergic Drugs (agonist) Adrenergic Antagonist (Chapter 4) Antihistamines Histamine H1 Receptor Antagonists Local Anesthetics

3.1 Cholinergic Drugs(拟胆碱药) ° Cholinergic effect Mediated by acetylcholine (ACh) N Acetylcholine

3.1 Cholinergic Drugs （拟胆碱药） • Cholinergic effect Mediated by acetylcholine （ACh）

Biosynthesis of acetylcholine Serine Choline COoH decarboxylase N-methyltransferase NH. HO )NH2 Choline acetyltransferase AcylCholine

Biosynthesis of Acetylcholine

The Classification of Cholinergic Drugs Cholinoceptor agonists Cholinergic Drugs Acetylcholinesterase inhibitors (AChEIs

The Classification of Cholinergic Drugs Acetylcholinesterase inhibitors (AChEIs) Cholinocepter agonists Cholinergic Drugs

31.1 Cholinocepter agonists(胆碱受体激动剂) Cholinergic receptor M-receptor Muscarine (毒蕈碱) -receptor Nicotine (烟碱)

3.1.1 Cholinocepter agonists(胆碱受体激动剂) Cholinergic receptor • M-receptor Muscarine (毒蕈碱) • N-receptor Nicotine (烟碱)

Cholinocepter agonists O NH O′NH Carbachol(卡巴胆碱) Bethanechol chloride(氯贝胆碱) HO o Muscarine N、 Acetylcholine

Cholinocepter agonists

SAR of Cholinocepter agonists Acyloxy group Quaternary ammonium H3CO-CH2-CH2+-N(CH3)Cl Ethylene group Ing's rule of five This rule suggests that there should be no more than five atom between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency

SAR of Cholinocepter agonists Ing’s rule of five: This rule suggests that there should be no more than five atom between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency

1. The molecule possesses a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt 2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of methyl group 3. The molecule should have an oxygen atom preferably an ester-like oxygen, capable of participating in a hydrogen bond 4. There should be a two-carbon unit between the oxygen atom and the nitrogen atom Acyloxy group Quaternary ammonium o H3co+cH2—cH2N(cH3)c Ethylene group

• 1. The molecule possesses a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt. • 2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of methyl group. • 3. The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond. • 4. There should be a two-carbon unit between the oxygen atom and the nitrogen atom

Me> h and bulky group R2=Me, decrease N-effect Triethyl substitution displays M-effect retains anticholinergic effect carbamoyl substitution is stable 2 R Et or ph substitution cation Is important lower activity R As( CH3)3, S(CH3)2 Se(Ch3)2 subtitution decrease the acitivity R3=Me, inhibit AChE N-effect> M-effect