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Medicinal Chemistry Chapter 3

Medicinal Chemistry Chapter 3. Peripheral Nervous System Drugs. Outline. Cholinergic Drugs. Drug Affecting Cholinergic Neurotransmission. Anticholinergic Drugs. Adrenergic Drugs (agonist). Drug Affecting Adrenergic Neurotransmission. Adrenergic Antagonist (Chapter 4). Antihistamines.

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Medicinal Chemistry Chapter 3

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  1. MedicinalChemistryChapter 3 Peripheral Nervous System Drugs

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

  3. 3.1 Cholinergic Drugs （拟胆碱药） • Cholinergic effect • Mediated by acetylcholine （ACh）

  4. Biosynthesis of Acetylcholine

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

  6. 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)

  7. Cholinocepter agonists

  8. 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.

  9. 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.

  10. Bethanechol Chloride （氯贝胆碱） 2-[(Aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium chloride

  11. Actions and Uses • Potent muscarinic agonist. Orally effective, also administered by subcutaneous (皮下) injection. • Increased hydrolytic stability (carbamate and steric bulk) • Stimulant of GI tract smooth muscle and urinary bladder. • Uses: For the relief of post-surgical urinary retention （尿潴留） and abdominal distention （腹胀）. • Low toxicity, no serious side effects. • Should be used with caution in asthmatic （哮喘的）patients.

  12. Bethanechol Chloride Synthesis:

  13. Future Muscarinic Agonists Current research interest is focused on developing agents with selective affinity for muscarinic receptors in the brain. Potentially useful in the treatment of Alzheimer’s disease （阿尔茨海默尔）and other cognitive disorders. e.g. Xamomeline (呫诺美林)

  14. 3.1.2 Acetylcholinesterase Inhibitors (AChEIs) Acetylcholinesterase (AChE) Inhibition of acetylcholinesterase (AChE) increases the concentration of acetylcholine (ACh) in the synapse. This results in prolonging the action of ACh, producing both muscarinic and nicotinic responses.

  15. Therapeutic Application of AChEIs • Indirect acting cholinergic agonists • Treatment of myasthenia gravis (重症肌无力), atony （弛缓） in the gastrointestinal tract and glaucoma （青光眼）. • Investigational therapy for Alzheimer’s disease • Agricultural insecticides and nerve gas warfare agents.

  16. Reversible AChEIs • Classical AChEIs • Nonclassical AChEIs

  17. Neostigmine Bromide （溴新斯的明） 3-[[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium bromide

  18. Actions and Uses • Chemically more stable than physostigmine （毒扁豆碱） • Longer duration of action • Administered orally or iv • The most frequent use of neostigmine is to prevent atony (张力迟缓) of the intestinal, skeletal, and bladder musculature. Also used as urinary stimulant.

  19. Tacrine（他克林） • Potent centrally acting AChE inhibitor • • FDA approved for the treatment of Alzheimer’s Disease • (To increase ACh levels in the brain) • • Side Effects: Hepatotoxicity; Abdominal cramping （腹部绞痛）

  20. New Non-Competitive AChEIs • Exhibit greater CNS AChE selectivity • Little or no hepatotoxicity

  21. 3.2 Anticholinergic Drugs （抗胆碱药） • Muscarinic antagonists • Nicotinic antagonists • Neuromuscular blocking agents (N2-receptor)神经肌肉阻断剂 • Ganglionic blocking agents （N1-receptor）神经节阻断剂

  22. 3.2.1 Muscarinic antagonists • Muscarinic antagonists are compounds that have high affinity for M-receptor but have no intrinsic activity. • Competitive (reversible) antagonists of ACh • •Antagonism responses include: decreased contraction of GI and urinary tract smooth muscles, dilation of pupils (扩张瞳孔), reduced gastric secretion, decreased saliva （唾液）secretion.

  23. Therapeutic Uses of Muscarinic antagonists • Treatment of smooth muscle spasms (肌痉挛) • Ophthalmologic （眼科）examinations • Treatment of gastric ulcers (胃溃疡) • Reduction of nasal and upper respiratory tract secretions in cold and flu

  24. Solanaceous Alkaloids （茄生物碱类） Found mainly in henbane (花烟草) (Hyoscyamus niger,莨菪属), deadly nightshade (龙葵属植物) (Atropa belladonna, 颠茄), and jimson weed (Datura stramonium，曼陀罗叶)

  25. • Belladonna Alkaloids: esters of tropic acid and tropine. • Parenteral preparations (quaternary derivatives) are more potent than the parent compounds. • Therapeutic uses: mydriatic （扩瞳药）; antispasmodic （解痉药）. • Side effects: dryness of mouth; urine retention（尿潴留）; blurred vision （视力模糊）; constipation （便秘）. • Atropine is an antidote （解毒药）to poisoning by organophosphorus pesticides （有机磷农药）.

  26. Atropine Sulfate - (Hydroxymethyl)benzeneacetic acid (3-endo)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl ester sulphate monohydrate

  27. Atropine • Atropine is (+)-hyoscyamine (莨菪碱), an ester of the tropic acid and tropine. • Vitali reaction for tropic acid • Natural product is (-)-hyoscyamine. Atropine results from the base-catalyzed racemization of the chiral carbon of tropic acid, which occurs during isolation process. • Antimuscarinic effect: • S(-)-Hyoscyamine > Atropine >> R(+)-Hyoscyamine

  28. Anisodanmine hydrobromide(氢溴酸山莨菪碱) (S)- (Hydroxymethyl)benzeneacetic acid 6β-hydroxy-1αH, 5αH-8-methyl-8- azabicyclo[3.2.1] oct-3 α -yl ester hydrobromide

  29. Synthetic Muscarinic antagonists • Administered orally or by parenteral routes • Therapeutic Use: Treatment of GI disorder (in combination with Librium (利眠宁), a tranquilizer) • Contraindicated (禁忌) in glaucoma (青光眼)

  30. Amino Alcohol Ester of Synthetic Muscarinic antagonists

  31. Anticholinergic Amino Alcohols

  32. Anticholinergic Amino Ethers

  33. Propantheline Bromide (溴丙胺太林) N-Methyl-N-(1-methylethyl)-N-[2-[(9H-xanthen(咕吨)-9-ylcarbonyl)oxy]ethyl]-2-propanaminium bromide

  34. Actions and Uses • Potent peripheral antimuscarinic effect • Weak Ganglionic (神经节的) blocking effect • Selectivity for Gastrointestinal tract • Treat or prevent spasm (痉挛) in the muscles of the gastrointestinal tract.

  35. Recent Muscarinic Antagonists Subtype selective muscarinic antagonists. • M1-selective antagonist • Clinical trials for the treatment of duodenal ulcers (十二指肠溃疡)

  36. Nicotinic Antagonists Two subclasses: • Ganglionic blocking agents (神经节传导阻滞剂) • (N1-receptor antagonist) • Skeletal neuromuscular blocking agents (骨骼肌神经肌肉阻滞药) (N2-receptor antagonist)

  37. Skeletal Muscular Relaxants （骨骼肌松弛药） • Central Muscular relaxants • Skeletal neuromuscular blocking agents • (N2-receptor antagonist) Chlorzoxazone (氯唑沙宗)

  38. Neuromuscular Blocking Agents • Classification: • Nondepolarizing (Competitive Neuromuscular Blocking Agents) : inactive on N2-receptor • Depolarizing (Noncompetitive Neuromuscular Blocking Agents) : to activate N2-receptor

  39. 极化状态：神经和肌纤维在静止状态时，其膜内呈负电位，膜外呈正电位，称“极化状态”。极化状态：神经和肌纤维在静止状态时，其膜内呈负电位，膜外呈正电位，称“极化状态”。 • 去极化：当正常神经冲动达到神经肌肉接头使神经末梢释放乙酰胆碱时，后者与运动板膜上的胆碱受体结合，促使膜对某些离子的通透性改变，使膜内外的电位差呈一时性消失，引起“去极化”，从而产生动作电位，导致肌肉收缩。

  40. 非去极化型：本型肌松药能竞争占膜上的胆碱受体，阻断乙酰胆碱的去极化，而其本身并不产生去极化作用，结果使骨骼肌松弛。可被抗胆碱酯酶药新斯的明所对抗。非去极化型：本型肌松药能竞争占膜上的胆碱受体，阻断乙酰胆碱的去极化，而其本身并不产生去极化作用，结果使骨骼肌松弛。可被抗胆碱酯酶药新斯的明所对抗。 • 去极化型：本型肌松药能与终板膜上的胆碱受体结合，产生去极化状态，且去极化状态较乙酰胆碱持久，导致终板对乙酰胆碱的反应性降低，因而也产生肌肉松弛。不被抗胆碱酯酶药新斯的明所对抗，而且加剧这种作用。

  41. 神经肌肉阻断剂：非去极化型和去极化型两大类。神经肌肉阻断剂：非去极化型和去极化型两大类。 • － 非去极化型肌松药容易调控，比较安全，临床用肌松药多为此类。 • － 去极化型肌松药起效快，持续时间短，如氯琥珀胆碱。 • － 具有去极化和非去极化双重作用，如溴己氨胆碱 ，起初发生短时间的去极化，接着产生较长时间的非去极化，适用于大手术。

  42. Specific Depolarizing Neuromuscular Blocking Agents Succinylcholine chloride (氯化琥珀酰胆碱) • Very short duration of action (iv) • Rapid hydrolyzed and rendered inactive by plasma esterase. • Use: Muscle relaxant. Suitable for short periods of relaxation. Suitable for continuous iv drip.

  43. Specific Nondepolarizing Neuromuscular Blocking Agents • d-Tubocurarine (筒箭毒碱) and Metocurine (甲筒箭毒) • Steroid Based Neuromuscular Blocking Agents • Tetrahydroisoquinoline (四氢异喹啉) Based Neuromuscular Blocking Agents

  44. d-Tubocurarine and Metocurine d-Tubocurarine （筒箭毒碱） • Plant alkaloid. Isolated from Chondodendron tomentosum.南美防己属 • • Causes muscle paralysis (arrow poison). • • only one quaternary ammonium group. • Administered intravenously and has a long duration of action. Primarily excreted as unchanged drug in the urine and bile. • • Therapeutic Use: As a muscle relaxant in various surgical procedures. Metocurine（甲筒箭毒碱） • A semi-synthetic analog of tubocurarine. • As a bis-quaternary ammonium compound, it is about four times more potent than the parent compound.

  45. Tetrahydroisoquinoline Based Neuromuscular Blocking Agents

  46. Atracurium Besylate (苯磺阿曲库铵) • A nondepolarizing neuromuscular blocker • The quaternary ammonium groups are located in two substituted tetrahydroisoquinoline rings separated by an aliphatic diester.(13 atoms) • Duration of action is slightly longer than that of succinylcholine (琥珀酰胆碱). • Metabolism: • Ester hydrolysis and Hoffmann elimination

  47. Metabolism: • Ester hydrolysis and Hoffmann elimination

  48. Steroid Based Neuromuscular Blocking Agents

  49. Pancuronium Bromide (泮库溴铵) 1,1′-[(2,3,5 ,16 ,17 )-3,17-Bis(acetyloxy) androstane-2,16- diyl] bis[1-methyl piperidinium]dibromide

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