UNIT 2

CHOLINOMIMETICS

STARS of the last week

هبةالبراك

خيرات الحناوي

نورة العويفي

ندىإمام

سارهالمتعب

مريم بدح

شروق الغامدي

LECTURE 2

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

SAR of Acetylcholine

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

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

SAR of Acetylcholine

• When CH3 groups were replaced by larger alkyl groups>>>> No activity

• When CH3 groups were replaced by hydrogen atoms >>>>> No activity

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.

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:

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

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:

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

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:

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

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

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

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

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

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

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