Download STRUCTURAL ACTIVITY RELATIONSHIP AMONG THE

STRUCTURAL ACTIVITY
RELATIONSHIP AMONG THE
CHOLINERGIC AND
ANTICHOLINERGIC AGENT
Cholinergic Agent
-A cholinergic drug is a drug that acts
on the peripheral nervous system,
the central nervous system, or both
and enhances the effects that are
mediated by acetylcholine
-Also known as para
sympathomimetic, is any chemical
which functions to enhance the
effects mediated by acetylcholine in
the central nervous system, the
peripheral nervous system, or both.
- It is also known as cholinergic agent,
para-sympathomimetic drug or
cholinergic agonist.
-It works in 2 ways;
-1. By acting directly & mimicking
the effects of acetylcholine at one
or more acetylcholine receptors
present in the body.
2. By acting indirectly by
blocking/inhibiting the enzyme
acetylcholine that is responsible for
the degradation/ hydrolysis of
acetylcholine
Cholinergic Receptors
Two types, determined by:
•Location
•Action once stimulated
Mechanism of Action
-Direct-acting (agonist) –Bind to
cholinergic receptors, causing
stimulation
-Indirect-acting –Inhibit the
enzyme “cholinesterase”
Indirect-Acting Cholinergic Agents
(Cholinesterase Inhibitors
-Reversible –Bind to cholinesterase
for a period of minutes to hours
-Irreversible –Bind to cholinesterase
and form a permanent covalent bond
–The body must make new
cholinesterase
Drug Effects of Cholinergic Agents
1. Effects seen when the PSNS is
stimulated.
2. Stimulate intestine and bladder
–Increased gastric secretions
–Increased gastrointestinal motility
–Increased urinary frequency
3. Stimulate pupil
–Constriction (miosis)
–Reduced intraocular pressure
4. Increased salivation and sweating
5. Cardiovascular effects
–Decreased heart rate
–Vasodilation
6. Respiratory effects
–Bronchial constriction, narrowed
airways
7. At recommended doses, the
cholinergics primarily affect the
MUSCARINIC receptors.
8. At high doses, cholinergics
stimulate the NICOTINIC receptors.
Therapeutic Uses
- Direct-Acting Agents
•Reduce intraocular pressure
•Useful for glaucoma and
intraocular surgery
-Examples: acetylcholine, carbachol,
pilocarpine
- Direct-Acting Agent—bethanechol
•Increases tone and motility of
bladder and GI tract
•Relaxes sphincters in bladder
and GI tract, allowing them to empty
•Helpful for postsurgical atony
of the bladder and GI tract
•
Indirect-Acting Agents
•Cause skeletal muscle contractions
•Used for diagnosis and treatment
of myasthenia gravis
•Used to reverse neuromuscular blocking
agents
•Used to reverse anticholinergic poisoning
(antidote)
Examples: physostigmine,
pyridostigmine
- Indirect-Acting Agent—donepezil
(Aricept)
•Used in the treatment of mild
to moderate Alzheimer’s disease.
•Helps to increase or maintain
memory and learning capabilities
Cholinergic Agents: Side Effects
Side effects are a result of overstimulation of the
PSNS.
•Cardiovascular:
–Bradycardia, hypotension, conduction
abnormalities (AV block and cardiac arrest)
•CNS:
–Headache, dizziness, convulsions
•Gastrointestinal:
–Abdominal cramps, increased
secretions, nausea, vomiting
•
•Respiratory:
–Increased bronchial secretions,
bronchospasms
•Other:
–Lacrimation, sweating,
salivation, loss of binocular accommodation,
miosis
Drug interactions
•Anticholinergics, antihistamines, and
sympathomimetics antagonize cholinergic
agents, resulting in decreased responses
Cholinergic Blocking Agentsantagonist ( Anticholinergic Agent)
-An anticholinergic drug is a drug or
an agent that competes with the
neurotransmitter "acetylcholine" for
its binding sites at synaptic junctions
thereby suppressing or inhibiting its
activity and thus preventing the
transmission of parasympathetic
nerve impulses.
-Depending on the type of receptor
to act on, anticholinergic drugs are
either classified as muscarinic
antagonists or nicotinic antagonists.
- They are compounds which prevent
acetylcholine from stimulating the
receptor site and thus act as
antagonists.
- Drugs that block or inhibit the actions
of acetylcholine (ACh) in the
parasympathetic nervous system (PSNS)
Mechanism of Action of Cholinergic
Blocking Agents
•Competitive antagonists
•Compete with ACh
•Block ACh at the muscarinic receptors in the
PSNS –As a result, ACh is unable to bind to the
receptor site and cause a cholinergic effect.
•Once these drugs bind to receptors, they
inhibit nerve transmission at these receptors.
Chemical class
Blocking Agents
- Natural
1. atropine
2. hyoscyamine
3. scopolamine
4.belladonna
of
Cholinergic
Synthetic/Semisynthetic
•
• anisotropine clidinium
•
dicyclomine glycopyrrolate
• hexocyclium
homatropine
•
ipratropium
isopropamide
•
•
•
oxybutynin
propantheline
tolterodine
tridihexethyl
Drug Effects of Cholinergic Blocking
Agents
•Cardiovascular
–Small doses: decrease heart rate
–Large doses: increase heart rate
•CNS
–Small doses: decrease muscle rigidity and
tremors
–Large doses: drowsiness, disorientation,
hallucinations
•Eye
–Dilated pupils (mydriasis)
–Decreased accommodation due to paralysis of
ciliary muscles (cycloplegia)
•Gastrointestinal
–Relax smooth muscle tone of GI tract
–Decrease intestinal and gastric
secretions
–Decrease motility and peristalsis
•Genitourinary
–Relaxed detrusor muscle
–Increased constriction of internal
sphincter
–Result: urinary retention
•Glandular
–Decreased bronchial secretions,
salivation, sweating
•Respiratory
–Decreased bronchial secretions
–Dilated bronchial airways
Therapeutic Uses of Cholinergic
Blocking Agents
♥
CNS
Decreased muscle rigidity and muscle tremors
•Parkinson’s disease
•Drug-induced extrapyramidal reactions
♥ Cardiovascular
Affect the heart’s conduction system
•Low doses: slow the heart rate
•High doses: block inhibitory vagal effects
on the SA and AV node pacemaker cells
–Result: increased heart rate
• ♥ Atropine
Used primarily for cardiovascular
disorders
•Sinus node dysfunction
•Symptomatic second-degree heart
block
•Sinus bradycardia with
hemodynamic compromise (advanced life
support)
♥ Respiratory
Blocking the cholinergic stimulation of the PSNS allows
unopposed action of the SNS.
•Results: –Decreased secretions from nose, mouth,
pharynx, bronchi
–Relaxed smooth muscles in bronchi and
bronchioles
–Decreased airway resistance
–Bronchodilation
Respiratory agents are used to treat:
•Exercise-induced bronchospasms
•Chronic bronchitis
•Asthma
•Chronic obstructive pulmonary disease
•
♥ Gastrointestinal
PSNS controls gastric secretions and smooth
muscles that produce gastric motility.
•Blockade of PSNS results in:
–Decreased secretions
–Relaxation of smooth muscle
–Decreased GI motility and
peristalsis
Gastrointestinal agents are used to treat:
•Peptic ulcer disease
•Irritable bowel disease
•GI hypersecretory states
•
♥ Genitourinary
•Relaxed detrusor muscles
of the bladder
•Increased constriction of
the internal sphincter
•Reflex neurogenic bladder
•Incontinence
Side effects
• Irritability
• disorientation
• halucination
• Decreased salivation
• Decreased sweating
• Decreased bronchial secretions
Drug Interactions
•
•Antihistamines, phenothiazines, tricyclic
antidepressants, MAOIs
•When given with cholinergic blocking
agents, cause ADDITIVE cholinergic effects,
resulting in increased effects
STRUCTURAL ACTIVITY
RELATIONSHIP
Definition
• The structure–activity relationship
(SAR) is the relationship between the
chemical or 3D (molecular) structure
of a molecule and its biological
activity.
• Structure-activity relationship is the
relationship between chemical
structure and pharmacological
activity for a series of compounds.
• SARS is the study of relationship
between a drug’s molecular
structure and the drug’s biological
activity.
• The Structure-activity relationship
(SAR) is a means by which the effect
of a drug or toxic chemical on an
animal, plant or the environment can
be related to its molecular structure.
• This type of relationship may be assessed by
considering a series of molecules and making
gradual changes to them, noting the effect
upon their biological activity of each change.
• The rationale behind SAR is that the structure
of the chemical implicitly determines its
physical and biological properties and
reactivity, which in interaction with a
biological system, determine its biological /
toxicological properties .
• Therefore, the science of SAR is in
relating the structure to activity, i.e.
identifying the key aspects of
structure, pertaining to the
molecular event(s) in the mechanism
of action for the chemical or
biological actions of interest.
Pharmacological Effects Of Sars
• 1.SARS have made it possible to map out the
receptor and prepare a model that can
account for the affinity and the intrinsic
activity of cholinergic agonist and anticholinergic.
2.
The analysis of SAR enables the
determination of the chemical group
responsible for evoking a target
biological effect in the organism
• 3. Structure-activity studies are
critical to designing a pharmaceutical
with the greatest potency and least
side effects.
HISTORY
• Brown and Fraser in 1869 showed
that many compounds containing
tertiary amine groups became
muscle relaxants when converted to
quaternary ammonium compounds.
• This hypothesis was later rejected.
“Molecules that block the effects of natural
neurotransmitters (antagonists) generally are
larger in size than the native compound.
Features Of SAR of Cholinergics
• A molecule must possess a nitrogen
atom capable of bearing a positive
charge, preferably a quaternary
ammonium salt.
• For maximum potency, the size of
the alkyl groups substituted on the
nitrogen should not exceed the size
of a methyl group.
• The molecule should have an oxygen
atom, preferably an ester-like oxygen
capable of participating in a hydrogen
bond.
• A two-carbon unit should occur
between the oxygen atom and the
nitrogen atom.
• There must be two methyl groups on
the nitrogen
• A larger third alkyl group is tolerated
but more than one large alkyl groups
leads to loss of activity
• There should be no more than five
atoms between the nitrogen and the
terminal hydrogen for muscarinic (or
cholinergic) activity; for maximum
potency, the size of the alkyl groups
substituted on the nitrogen should
not exceed the size of a methyl
group;
• The molecule should have an oxygen atom,
preferably an ester-like oxygen capable of
participating in a hydrogen bond;
• There should be a two-carbon unit between
the oxygen atom and the nitrogen atom.
STRUCTURAL ACTIVITY OF
ANTICHOLINERGICS
• With respect to the acid moiety of
the anticholinergics, the following
structure-activity relationships are
found:
• 1. As R1 is increased from methyl to
higher alkyls or becomes hydrogen,
alkenyl, amino, or aminoalkyl,
psychotropic potency diminishes
without much effect on peripheral
anticholinergic action.
• 2. R2 should be an unsubstituted phenyl
group, wherase R3 must be either a cycloalkyl,
alkynyl, thienyl, or unsubstituted phenyl. Alkyl,
aryl, halide, or hydroxyl substituents on the
phenyl rings abolish central action and
diminish anticholinergic potency. R2 and R3
can also be replaced by hexahydrofluorenyl
• 3. The position of the ester side chain affects
central, but not peripheral action, with the 4piperidyl ester being most potent, the 3-ester
second most and the 2-ester least.
• 4. R4 must be a hydroxyl group, whereas
compounds with hydrogen or an isosteric
methyl group are devoid of central action and
have diminished anticholinergic action. If R4 is
hydrogen and the hydroxyl group is present on
phenyl, central potency is retained.
DESCRIPTION OF SAR AMONG
CHOLINERGIC AND ANTICHOLINERGIC
AGENTS
1) Methacholine
Name: Methacholine
Type of Agent: Direct Muscarinic Agonist
SAR:
1. Quaternary Amine - Charged , hydrophilic and
Cannot cross BBB
2. Beta-methyl - longer-acting effect, Muscarinic
selectivity
3. Ester - susceptible to esterase, smaller methyl
preferred (larger = low affinity)
Indications:
•
Diagnose bronchial hyperactivity ONLY Patient inhales aerosolized Methacholine
(broncoconstriction)
Should NOT be used as a therapeutic agent
2) Carbachol
• Name: Carbamolycholine
(Carbachol)
Type of Agent:
Direct Muscarinic Agonist
SAR:
1. Quaternary Amine - Charged ∴ Hydrophilic,
cannot cross BBB
2. Carbamate - Slows down hydrolysis (longlasting)
3. Hydrogen bonding
Indications:
Glaucoma - Decrases pressure in eye for those
with glaucoma
Miosis during cataract surgery
3) Pilocaripine
Name: Pilocaripine
Type of Agent: Direct Muscarinic Agonist
SAR:
1. Chiral Carbon - allows epimerization, allows
for substiuents to change sterochemistry, can
be kept refrigerated to avoid epimerization
Indications:
Glaucoma
Dry mouth (after radiation)
Adverse Effects:
Visual changes
5) Neostigmine
Name: Neostigmine
Type of Agent: Indirect Acting AChE inhibitor
SAR:
•
Quaternary Amine - charged ∴ hydrophilic,
can't cross BBB
Carbamate - slows down hydrolysis ∴ long
lasting
Hydrogen bonding
Indications:
•
Myasthenia Gravis - Decrease in release of
ACh and less nACh receptors
Urinary retention
Reverse neuromuscular blockage
Adverse Effects:
•
Allergenic cross-reactivity for ChE inhibitors
Contraindications Hypersensitivity
7) : Physostigme
• Name: Physostigme
Type of Agent: Indirect Acting AChE inhibitor
SAR:
Carbamate - slows down hydrolysis ∴ long-acting
Hydrogen Bonding
Indications:
•
Glaucoma
Reversal of CNS anticholinergic syndrome
Adverse Effects:
•
Contraindications GI obstruction
Asthma
Diabetes
CV disease
Coadministration of choline esters and
depolarizing neuromuscular-blocking agents
8) SCOPOLAMINE
Name: Scopolamine (Isopto Hyoscine)
Type of Agent: Muscarinic Antagonist
SAR:
Acyloxy - ethylene - quaternary amine
• Indications:
Transdermal - prevent N/V
Adverse Effects:
Anaphylaxis
Bradycardia
CNS effects
Visual disturbances
9) Tubocurrarine
• Name: D-Tubocurrarine(Curare)
Type of Agent: Nicotinic Antagonist
SAR:
1. Bis-quaternary ammonium
Not absorbed orally
• Indications:
nondepolarizing blocker - Death occurs
through respiratory paralysis
Muscle relaxant during surgery
Adverse Effects:
Trigger histamine release - BP drops
Tubocurarine
MeO
Me
N
HO
Me
H
O
Me
H
H
CH2
CH2
O
N
OH
OMe
ATROPINE
Name: Atropine (Isopto Atropine)
Type of Agent: Muscarinic Antagonist
SAR:
Acyloxy - Ethylene - Quaternary Amine
Chiral Carbon, Diasteromeric mixture
L-isomer is physiologically active
ATROPINE
Indications:
•
Ophthalmic - Mydriasis
Before anaesthesia - prevent hypersecretion of
bronchial mucus
ACh inhibitor and mushroom poisoning
Adverse Effects:
Elevated BP
Photophobia/blurred vision
PRACTISE QUESTIONS
• a. Describe the structure-activity relationship
of TWO anticholinergic drugs.
• b. Compare and contrast the
pharmacokinetics and pharmacodynamics of
atropine and pilocarpine.
•