1. CHOLINERGIC AGENTS 2. Cholinergic Antagonists
Medicinal Chemistry III / lecture 2
Shokhan J. Hamid
21/10/2018

2. Muscarinic
Antagonist
Cholinergic agents
Nicotinic
Antagonist

3. muscarinic antagonist
An agent that have high binding affinity for the muscarinic receptor but have no intrinsic activity.
they compete with Acetylcholine to occupy muscarinic receptor.
They are competitive (reversible) antagonists of acetylcholine.
Their pharmacological effects are opposite to that of the muscarinic agonists.
antagonist

4. Therapeutic Actions
Mydriatic effect: dilation of the pupil of the eye; and cycloplegia.
2. Antispasmodic effect: lowered tone and motility of the GI tract and the genitourinary tract.
3. Antisecretory effect: reduced salivation, reduced perspiration, and reduced gastric secretion.

5. Therapeutic applications of antimuscarinics

6. Structure Activity Relationship
Acetyl CH3 group is
substituted with at
least one phenyl ring
for antimuscarinic
activity

7. Substitutions at α-carbon with respect to ester group

8. Changes at ester group

9. Substitution at the amine group

10. Changes at R4 position

11. SPECIFIC ANTIMUSCARINIC DRUGS:
1-solanaceous alkaloids and analogs: - Atropine - Hyoscyamine - Scopolamine - Homatropine Hydrobromide - Ipratropium Bromide - Tiotropium Bromide

12. SPECIFIC ANTIMUSCARINIC DRUGS:
Atropine: Classic Prototype for Antimuscarinics
The naturally occurring alkaloid, It occurs naturally in various Solanaceae
Uses:
Decrease GIT motility
Dilation of pupil
Its ability to dry secretions has also been used in the so called rhinitis for symptomatic relief in colds.
Atropine may be used to treat some types of arrhythmias. It increases the heart rate by blocking the effects of Ach. In this context, it is used to treat certain reversible bradyarrhythmias that may accompany acute myocardial infarction.
Atropine is a specific antidote to prevent the muscarinic effects of ACh accumulation

13. Scopalamine (Hyoscine)
Scopolamine is a competitive blocking agent of the parasympathetic nervous system as is atropine.
Both drugs readily cross the blood-brain barrier and, even at therapeutic doses, cause confusion, particularly in the elderly.
Used in the treatment of motion sickness.

14. Antimuscarinic drugs used in the treatment of bronchial asthma
Ipratropium hydrobromide:
N-isopropyl analogue of Atropine
Quaternary cationic nature makes it highly hydrophilic and poorly absorbed from the lungs after inhalation via solution or aerosol, so bronchodilation effect can be considered to be a local, site-specific effect
Ipratropium bromide is used in inhalation therapy to produce dilation of bronchial smooth muscle for acute asthmatic attacks.
Reaches the circulation minimally and is partially metabolized by esterases to inactive product.

15. Tiotropium Bromide Dithienyl derivative of N-methyl scopolamine.
Longer duration of action than ipratropium (24 versus <4 hours, respectively).
It is indicated in the treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
Tiotropium is metabolized by both CYP3A4 and CYP2D6, followed by glutathione conjugation.

16. 2- synthetic cholinergic blocking agents:
A- Aminoalcohol Esters:
Clidinium Bromide
Cyclopentolate Hydrochloride
Dicyclomine Hydrochloride
Eucatropine Hydrochloride
Glycopyrrolate
Mepenzolate Bromide
Methantheline Bromide
Oxyphencyclimine Hydrochloride
Propantheline Bromide
Oxybutynin
Trospium Chloride
Solifenacin Succinate

17. B- Aminoalcohol Ethers: Benztropine Mesylate Orphenadrine Citrate
B- Aminoalcohol Ethers: Benztropine Mesylate Orphenadrine Citrate. C- Aminoalcohols: Biperiden Procyclidine Tridihexethyl Chloride Trihexyphenidyl Hydrochloride Tolterodine D- Aminoamides: Isopropamide Iodide Tropicamide Darifenacin Hydrobromide E- Miscellaneous: Diphemanil Methylsulfate Ethopropazine Hydrochloride Papaverine Hydrochloride

18. The Pharmacophore for all classes of antimuscarinics

19. A- Clidinium Bromide
This anticholinergic agent is marketed alone and in combination with the minor tranquilizer chlordiazepoxide (Librium) in a product known as Librax.
The rationale of the combination for the treatment of GI complaints is the use of an anxiety-reducing agent together with an anticholinergic agent, based on the recognized contribution of anxiety to the development of the diseased condition.
It is used for peptic ulcer, hyperchlorhydria, ulcerative or spastic colon, anxiety states with GI manifestations, nervous stomach, irritable or spastic colon.

20. Oxybutynin
Oxybutynin acts as a competitive antagonist on M1, M2, and M3 receptor subtypes.
it has direct spasmolytic effects on bladder smooth muscle.
This reduction in smooth muscle tone allows for greater volumes of urine to be stored in the bladder, which results in less urinary incontinence, urgency, and frequency.

21. B- Orphenadrine
It does reduce voluntary muscle spasm, however, by a central inhibitory action on cerebral motor areas, a central effect similar to that of atropine.

22. C- Tolterodine
It is an antimuscarinic agent that acts on M2 and M3 muscarinic subtype receptors.
By competitively blocking of the muscarinic receptors results in a reduction of the smooth muscle tone, allowing for greater volume of urine to be stored in the bladder.
This results in less urinary incontinence, urgency, and frequency
Known Side Effects: Hyposalivation(Dry mouth), decreased gastric motility, headache, constipation, dry eyes ..

23. Procyclidine
Its clinical usefulness lies in its ability to relieve voluntary muscle spasticity by its central action.
Therefore, it has been used with success in the treatment of Parkinson disease.

24. D- Darifenacin Selective M3 antagonist
By competitively blocking of the muscarinic receptors results in a reduction of the smooth muscle tone, allowing for greater volume of urine to be stored in the bladder.
This results in less urinary incontinence, urgency, and frequency.
first

25. Tropicamide is an effective anticholinergic for ophthalmic use.
Mydriasis

26. NICOTINIC ANTAGONISTS
Compounds that bind to cholinergic nicotinic receptors with no intrinsic efficacy (competitive antagonists with Ach)
Two subclasses of nicotinic antagonists
◦ Ganglionic blocking agents.
◦ Neuromuscular blocking agents.

27. Ganglionic Blocking Agents
1- Depolarizing Ganglionic Blocking Agents 2- Nondepolarizing Competitive Ganglionic Blocking Agents 3- Nondepolarizing Noncompetitive Ganglionic Blocking Agents

28. Neuromuscular blocking agents
Agents that block the transmission of ACh at the motor end plate are called neuromuscular blocking agents.
The therapeutic use of these compounds is primarily as adjuvants in surgical anesthesia to obtain relaxation of skeletal muscle.
Non-depolarizing blocking agents
Depolarizing blocking agents
Curare and curare alkaloids

29. Curare and curare alkaloids
Tubocurarine Chloride; the first neuromuscular blocker
Tubocurarine is a nondepolarizing blocking agent used for its paralyzing action on voluntary muscles.

30. SAR
Bis‐quaternary ammonium compound, having two quaternary ammonium salts separated by 10 to 12 carbon atoms (similar to the distance between the nitrogen atoms in tubocurarine) was a requirement for neuromuscular blocking activity.

31. Depolarizing agents
Decamethonium Bromide
Succinylcholine Chloride

32. Non-depolarizing agents
Aminosteroids
Pancuronium bromide
Vecuronium bromide
Rocuronium bromide
Pipecuronium bromide
Tetrahydroisoquinolines
d‐Tubocurarine and metocurine
Atracurium besylate
Cis‐atracurium
Mivacurium chloride
Doxacurium chloride

33. Pancuronium Bromide It is a typical nondepolarizing blocker
The principal use of pancuronium bromide is as an adjunct to anesthesia, to induce relaxation of skeletal muscle, but it is also used to facilitate the management of patients undergoing mechanical ventilation.

34. Vecuronium bromide
It belongs to the class of nondepolarizing neuromuscular blocking agents and produces effects similar to those of drugs in this class.

35. Atracurium
is a nondepolarizing neuromuscular blocking agent that is approximately 2.5 times more potent than d-tubocurarine.

36. SAR summery Contain at least one +ve charged quaternary amine
Bis quaternary amines:
Succinylcholine, Pancuronium, Atracurium
Mono quaternary amines:
Vecuronium, Rocuronium
10‐12 carbon bridge between two nitrogens is optimal for maximal neuromuscular blockade.

37. END