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

Muscarinic Antagonist Cholinergic agents Nicotinic Antagonist

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

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.

Therapeutic applications of antimuscarinics

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

Substitutions at α-carbon with respect to ester group

Changes at ester group

Substitution at the amine group

Changes at R4 position

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

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

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.

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.

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.

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

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

The Pharmacophore for all classes of antimuscarinics

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.

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.

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.

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 ..

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.

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

Tropicamide is an effective anticholinergic for ophthalmic use. Mydriasis

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.

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

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

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

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.

Depolarizing agents Decamethonium Bromide Succinylcholine Chloride

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

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.

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

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

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.

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