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811 > Lectures 30/31 > Flashcards

Lectures 30/31 Flashcards

Cholinomimetics - Feng

1
Q

Cholinomimetics

A
  • Transmission of impulses throughout cholinergic NS is mediated by ACh
  • Compounds that produce ACh’s pharmacological effects by mimicking for ACh = cholinergics
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2
Q

Cholinergics Therapeutics

A
  1. Relief of post-operative muscular weakness of gut and urinary bladder
  2. Reduction of IOP in some glaucomas
  3. Relief of muscular weakness in myasthenia gravis
  4. Relief of symptoms of Alzheimer disease
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3
Q

ACh

A
  • Organic cation that acts on neurotransmitters in PNS and CNS
  • Ester of acetate and choline
  • *Recognize structure**
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4
Q

Neurochemistry of ACh

A
  • Serine decarboxylase takes serine and converts it to choline
  • Choline is recycled by ChAT into ACh
  • 2 sources of choline: synthesis from serine and recycling from ACh hydrolysis (50%)
  • ACh can be used intracellularly and extracellularly
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5
Q

Cholinergic Receptors

A
  • Not all chol. receptors are identical
  • Two types: nicotinic and muscarinic
  • Named after natural product showing receptor selectivity
  • L-+-Muscarine - activates chol. receptors on smooth and cardiac muscle recognize structure
  • Nicotine activates chol. receptors in nervous system and skeletal muscle Know structure
  • Neither agonist is native in body, artificial
  • Both types can be activated by ACh - NON-SELECTIVE
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6
Q

Muscarine

A
  • Cyclic analog of ACh - carbonyl and Beta-C linked
  • Less flexible due to 5-membered ring in molecular skeleton
  • 3 chiral centers, but only muscarine is naturally occuring
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7
Q

Muscarine Receptor Models

A
  • G-coupled protein receptor
  • 5 different subtypes of receptors (M1-M5)
  • 7 hydrophobic, transmembrane, helical domains
  • 3 hydrophilic extracellular and intracellular loops each
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8
Q

Nicotinic Receptors

A
  • Ligand gated channels
  • Ion channels where ACh is the gate keeper
  • Modulates sodium and potassium ion concentrations
  • Multiple types of these receptors too
  • Two ACh bind to alpha subunits and their neighbors
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9
Q

ACh Stereochemistry

A
  • Doesn’t exhibit configurational isomers (no chiral centers)
  • Many agonist/antagonists are optical isomers (naturally occuring)
  • Therefore the stereochemistry is important for ACh
  • ACh receptors have chirality with antagonist/agonist effects connected to their stereochemistry
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10
Q

3-D Dimension

A

-This disposition of ACh is defined by torsion

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11
Q

Torsion Angle

A

Angle between two planes (plane containing A-B & B-C and plane containing C-D & B-C)

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12
Q

Structural (constitutional) Isomers

A

Compounds of the same molecular formula with different connectivity (structure, constitution)

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13
Q

Conformational Isomers

A

Compounds of the same structure that differ in rotation around one or more single bonds

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14
Q

Configurational Isomers

A

Compounds of the same structure that differ in one or more aspects of stereochemistry (how groups are oriented in space - enantiomers)

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15
Q

Conformations of ACh

A
  • Several freely rotatable single bonds
  • Large number of conformations
  • Active conformation is not necessarily the most stable
  • Many studies suggest that the main conformaiton is synclinal conformaiton
  • Expected to be antiperiplanar, but intramolecular interactions expected to be the cause of difference
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16
Q

Active Conformation

A
  • Rigid analogues of ACh
  • Rotatable bonds are “locked” in place with rings
  • Restricts the number of possible conformations
  • Defines separation of ester and nitrogen pharmacores
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17
Q

Ester and Nitrogen Distances for Receptors

A

Muscarinic - 4.4 A

Nicotinic - 5.9 A

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18
Q

Anticlinal Form

A
  • Conformation ACh is likely interacting with receptor in
  • Rigidly conformed in ACTM
  • Cis and trans isomers are synperiplanar and anticlinal respectively
  • Trans = potent, cis = no activity
  • Cis is more thermodynamically favorable though and may be favored in solution
  • *Adopts different state in different environments for stability or interaction purposes**
19
Q

ACh Pharmacologic Properties

A
  • Easily synthesized
  • Use: induces miosis in certain ocular surgeries
  • Formulations: IO and IV
  • ACh is highly susceptible in first pass metabolism
  • Quaternary amine makes it not easily absorbed through membranes (too polar)
  • Duration of action - 10-20 minutes, metabolized quickly by esterases
20
Q

Instability of ACh

A
  • Neighboring group activity (N+ — O(partial negative))
  • Increases the electrophilicity of carbonyl
  • Increases sensitivity to nucleophiles
  • Faster hydrolysis of esters (AChE)
21
Q

Categories of Cholinomimetic Drugs

A
  • Interacting with cholinergic receptors

- Increasing availability of ACh at sites

22
Q

Cholinoceptor Agonist

A
  • Directly acting
  • Activates Cholinoceptors
  • Choline esters (ACh, bethanechol) or alkaloids (pilocarpine)
23
Q

Anticholinoesterases

A
  • Indirectly act by inhibiting hydrolysis of ACh
  • Carbamates (physostigmine, neostigmine, edrophonium)
  • Phosphates (isoflurophate, antidote pralidoximine)
24
Q

Choline Esters

A
  • Requirement for chol. agonists
  • Stability to stomach acids and esterases
  • Selectivity for chol. receptors
  • Selectivity between mus. and nic. receptors
25
Q

Structural Variations of ACh

A
  • 4 possible sites to variate ACh since ACh is a poor therapeutic agent on its own
    1. Modification of quatenary ammonium
    2. Modification of ethylene bridge
    3. Modification of acyloxy group (R-CO)
    4. Substitution of ester group by other groups
26
Q

Modification of Quaternary Ammonium Options

A
  1. Replacement of nitrogen by other atoms

2. Replacing N-Me by H, N, O, or an alkyl

27
Q

Replacing Nitrogen

A
  • Only compounds with positive charge on atom in position of nitrogen had appreciable mus. activity
  • ALL nitrogen atom substituted compounds have less activity than ACh
  • Conclusions: positive charge is important for reactivity and don’t change the quaternary ammonium
28
Q

Replacing N-Me

A
  • Replacement of one N-Me by ethyl permits retention of chol, activity, more ethyl replacements decrease activity
  • Replacement with larger compounds loses almost all activity
  • Replacement with hydrogens leads to successive activity loss with each addition
  • Conclusions: N,N,N-trimethyl quaternary ammonium of ACh is optimum for potency, therefore nothing better than N-(Me)3 group, need at LEAST 2 Me on N
29
Q

Modifications of Ethylene Bridge

A
  • Five-atom rule: need to have 5 atoms between quart. N and terminal H to maximize mus. activity
  • Less atoms has similar effects but less potency than ACh
  • More atoms causes activity to rapidly be lost
  • Therefore distance is important for receptor binding and activity
30
Q

Modifying Ethylene Bridge - Adding Methyl

A
  • Acetyl - B - Methylcholine (methacholine) has similar muscarinic potency to ACh, used clinically
  • Methyl in the alpha position is more potent for nicotinic than muscarinic activity, but less potent than ACh in both
  • Difference arises from the methyl in the beta position acting as a steric shield to protect ester from nucleophiles and enzymes
  • Shield size and positioning is important, methyl is preferred, needs to be large enough to hinder esterase hydrolysis and small enough to hit in receptor binding site
31
Q

Methacholine

A
  • Placement of Methyl inhibits esterase binding and acts as a shield for nucleophilic attack
  • 3x more stable than ACh
  • Increasing the shield size increases its stability but decreases its activity
  • Selective for mus. over nic. receptors
  • S-enantiomer is more active than R, S matches muscarinic receptors (not selective for spec. subtypes)
32
Q

Modification of Acloxy (R-(C=O)O)

A
  • Carbamic acid esters (carbamate ester) of choline is more potent than acetates
  • Major advantages since it increases the stability and decreases AChE hydrolysis
  • Stabilizes carbonyl group of carbamate by delocalizing N’s lone pair onto carbonyl
33
Q

Carbamate Esters Properties

A
  • Resistant to hydrolysis, long acting
  • NH2 and CH3 are similar in size, fit in hydrophobic pocket, similar chemical and therefore biological properties
  • Muscarinic activity is equal to nicotinic activity
  • Used topically for glaucoma
34
Q

Carbamate Ester Steric + Electronic Properties

A
  • Not hydrolyzed reading by ChE, long duration
  • Orally active tablets
  • S-isomer is selective for muscarinic activity, almost 1000x more potent than R-enantiomer, similar to methacholine
  • Stimulates GI tract and urinary bladder after surgery
  • EX: Bethanechol
35
Q

Other Acetyl Group Replacements

A
  • Replacing with a larger or smaller group will be less potent than ACh
  • Extension of 5 atom rule
  • Can’t extend the molecule, only replace with NH2
36
Q

Substitution of Ester

A
  • Not essential for chol. activity
  • Many alkyl ethers of choline and thiocholine have chol. activity but are less potent
  • Not as capable of hydrogen bonding
  • Conclusions: Ester is still important for chol. activity
37
Q

SAR- Muscarinic Agonist

A
  • Based on quart. ammonium, ethylene bridge, and ester/acyloxy group
  • Methyl at B-carbon has increases mus. potency than nic.
38
Q

Muscarinic Agonist Physicochemical and PK Properties

A
  • Quart. and non-quart. ammonium salts are water soluble
  • Quart. chlorides and poorly orally soluble
  • Ester, lactone, and carbamates are relatively stable in aqueous media but prone to hydrolysis
39
Q

SARs for ACh Agonist

A
  1. Molecule must have positively charged N
  2. Size of alkyl groups subbed on N should not be larger than a methyl
  3. Should be oxygen atom, preferably ester-like oxygen capable of hydrogen bonding
  4. Should be 2-C unit between N & O
40
Q

Conclusions of ACh Modifications

A
  • Tight fit between ACh and binding
  • Methyl groups fit into small hydrophobic pockets
  • Esters interacting by hydrogen bonding
  • Quart. N interact by ionic binding
41
Q

Alkaloids

A
  • Cholinergic but not similar to ACh
  • Naturally occurring and contains N
  • Don’t conform with definition of synthetic sompounds not found in plants, closely related to natural alkaloids
42
Q

Pilocarpine

A
  • Example of an alkaloid
  • Extracted from leaves
  • Used for glaucoma as miotics
  • Mus. agonists to constrict pupil and increase aqueous flow
43
Q

Nicotine

A
  • Example of alkaloid
  • Bicyclic molecule
  • Basic with pKa of 8.5
  • Tight binding account for by similarities between ACh and nicotine
44
Q

Do all cholinomimetic drugs contain choline esters?

A

No. Many naturally and synthetic cholinomimetic drugs don’t have choline esters.

811 (38 decks)

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