unit 2 cholinomimetics. stars of the last week هبة البراك هبة البراك خيرات...
TRANSCRIPT
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UNIT 2
CHOLINOMIMETICS
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STARS of the last week
هبةالبراك
خيرات الحناوي
نورة العويفي
ندىإمام
سارهالمتعب
مريم بدح
شروق الغامدي
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LECTURE 2
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INTRODUCTION
• The mode of action of direct cholinomimetics involves binding to cholinergic receptors.
• Their discovery required an extensive study of the structural features required for the action of Acetylcholine.
Cholinomimetic drugs
Direct Indirect
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SAR of Acetylcholine
• To review the SAR of acetylcholine it is useful to divide the structure into the three components shown:
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SAR of Acetylcholine
1- Modification of the quaternary ammonium group.:
The effect of change in this group affects the muscarinic activity as following:• When N was replaced with AR, P or S >>>>> No activity
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SAR of Acetylcholine
• When CH3 groups were replaced by larger alkyl groups>>>> No activity
• When CH3 groups were replaced by hydrogen atoms >>>>> No activity
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SAR of Acetylcholine
2- Modification of the ethylene bridge:
• Replacement of ethylene group with larger groups>>>decrease activity
According to Ing`s Rule (rule of five): there should be no more than 5 atoms between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency.
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SAR of Acetylcholine
• Replacement of the hydrogen atoms of the ethylene bridge by alkyl groups larger than methyl >>>>> decrease activity
• A methyl group on the carbon α to the quat. N>>>> decreases activity
• A methyl group on the carbon β to the quat. N >>>>increase activity. The new drug was called..Methacholine:
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Methacholine
-It has muscarinic potency equivalent to Acetylcholine.- -It`s muscarinic potency more than nicotinic.
Uses: Mysthenia gravis, paroxysmal tachycardia
Disadv.: -still highly hydrophilic - Short duration(rapid hydrolysis)
H3C O
N (CH3)3
O
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SAR of Acetylcholine
3- Modification of acyloxy group:• Replacement of CH3(carboxylate)with NH2(carbamate)>>>>
resist hydrolysis by estrases ..Why?Carbamates are more stable than carboxylate ester to hydrolysis, because the carbonyl carbon is less electrophilic.
• The produced drug was named Carbachol:
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Carbachol
-It is less readily hydrolyzed in the GIT or by AChE than Ach >>>> administered orally
Uses: glaucoma
Disadv.: - -still hydrophilic - not selective
H2N O
N (CH3)3
O
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SAR of Acetylcholine
4- Modification of both acyloxy group and methylene bridge:• To collect the advantages of methacholine and carbachol,
another drug was made that have the advantage of high selectivity with more resistance to hydrolysis..
• It was named Bethanechol:
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Bethanechol
-It is the carbamate ester of Methacholine -It is an orally effective potent muscarinic agonist
Uses: - postsurgical & postpartum urinary retention - Abdominal distension
Disadv.: -Cholinergic crisis ( can not be given by I.V. or I.M. routes)
H2N O
N (CH3)3
O
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Non-classic cholinomimetics
• Scientists conducting the previous researches did not have the luxury of modern, highly refined biologic testing systems:
1- protein binding assays
2- cell mb. Binding assays
3- single-cell models
• For that, some muscarinic agonists did not adhere to this
SAR.
• Examples are: Pilocarpine and Xanomeline
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Pilocarpine
-It is a muscarinic agonist that does not adhere to the traditional SAR :
Uses: - -open-angle glaucoma- acute angle closure attacks
- xerostomia- Sjogren`s syndrome
Disadv:. Its lactone nucleus undergo hydrolysis into inactive pdct .
N
N
O
CH2CH3
O
CH3
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Xanomeline
-It is a muscarinic M1/M4 agonist
Uses: Alzheimer`s disease
Disadv.: not tolerated orally but transdermal delivery systems are showing promise.
N
N N
S
O
CH3
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Non-classic cholinomimetics
• Scientists conducting the previous researches did not have the luxury of modern, highly refined biologic testing systems:
1- protein binding assays
2- cell mb. Binding assays
3- single-cell models
• For that, some muscarinic agonists did not adhere to this
SAR.
• Examples are: Pilocarpine and Xanomeline
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Pilocarpine
-It is a muscarinic agonist that does not adhere to the traditional SAR :
Uses: - -open-angle glaucoma- acute angle closure attacks
- xerostomia- Sjogren`s syndrome
Disadv:. Its lactone nucleus undergo hydrolysis into inactive pdct .
N
N
O
CH2CH3
O
CH3
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Xanomeline
-It is a muscarinic M1/M4 agonist
Uses: Alzheimer`s disease
Disadv.: not tolerated orally but transdermal delivery systems are showing promise.
N
N N
S
O
CH3