1. UNIT 2
CHOLINOMIMETICS

2. STARS of the last week نورة العويفي ندى إمام خيرات الحناوي هبة البراك
ساره
المتعب
شروق الغامدي
مريم بدح

3. LECTURE 2

4. INTRODUCTION
Cholinomimetic drugs
Direct
Indirect
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.

5. SAR of Acetylcholine
To review the SAR of acetylcholine it is useful to divide the structure into the three components shown:

6. 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

7. SAR of Acetylcholine
When CH3 groups were replaced by larger alkyl groups>>>> No activity
When CH3 groups were replaced by hydrogen atoms >>>>> No activity

8. 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.

9. 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:

10. 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)

11. 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:

12. Carbachol
- It is less readily hydrolyzed in the GIT or by AChE than Ach >>>> administered orally Uses: glaucoma Disadv.: - -still hydrophilic - not selective

13. 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:

14. 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)

15. 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

16. 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.

17. Xanomeline
- It is a muscarinic M1/M4 agonist Uses: Alzheimer`s disease Disadv.: not tolerated orally but transdermal delivery systems are showing promise.

18. 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

19. 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.

20. Xanomeline
- It is a muscarinic M1/M4 agonist Uses: Alzheimer`s disease Disadv.: not tolerated orally but transdermal delivery systems are showing promise.