Cholinergic Drug Lecture 4, 5 &6

Cholinergic Drug Lecture 4, 5 &6
By Nohad A AlOmari Atrushi 14 تشرين الثاني، 18

1. Review to lecture 1 & 2 2. SAR of ACH 3
1. Review to lecture 1 & 2 2. SAR of ACH 3. Binding affinity of ACH to Cholinergic receptor : 4. COLINERGIC DRUGS Classifications Contents: 14 تشرين الثاني، 18

Peripheral nervous system
Skeletal Muscle SOMATIC CNS (Somatic) (Autonomic) Ach (N) Synapse AUTONOMIC Smooth Muscle Cardiac Muscle Ach (N) NA Adrenal medulla Sympathetic Parasympathetic Adrenaline Ach (N) Synapse Ach (M) Ach (N) 14 تشرين الثاني، 18

Cholinergic agonists Acetylcholine as an agonist Advantages
Natural messenger Easily synthesised Disadvantages Easily hydrolysed in stomach (acid catalysed hydrolysis) Easily hydrolysed in blood (esterases) No selectivity between receptor types No selectivity between different target organs 14 تشرين الثاني، 18

.SAR for acetylcholine Quaternary nitrogen is essential
Acetoxy 4 o Nitrogen Acetoxy Ethylene bridge Nitrogen Quaternary nitrogen is essential Bad for activity 14 تشرين الثاني، 18

SAR for acetylcholine Acetoxy Ethylene bridge Nitrogen Acetoxy Ethylene bridge 4 o Nitrogen Distance from quaternary nitrogen to ester is important Ethylene bridge must be retained Bad for activity 14 تشرين الثاني، 18

SAR for acetylcholine Ester is important Bad for activity Acetoxy
Ethylene bridge Nitrogen Acetoxy Ethylene bridge 4 o Nitrogen Ester is important Bad for activity 14 تشرين الثاني، 18

SAR for acetylcholine Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge 4 o Nitrogen Minimum of two methyl groups on quaternary nitrogen Bad for activity Active 14 تشرين الثاني، 18

SAR for acetylcholine Methyl group of acetoxy group cannot be extended
Ethylene bridge Nitrogen Acetoxy Ethylene bridge 4 o Nitrogen Methyl group of acetoxy group cannot be extended Bad for activity 14 تشرين الثاني، 18

SAR for acetylcholine Conclusions:
Acetoxy Ethylene bridge 4 o Nitrogen Conclusions: Tight fit between Ach and binding site Methyl groups fit into small hydrophobic pockets Ester interacting by H-bonding Quaternary nitrogen interacting by ionic bonding 14 تشرين الثاني، 18

Binding site (muscarinic)
Trp-307 Asp311 Trp-613 Trp-616 Asn-617 hydrophobic pocket pockets 14 تشرين الثاني، 18

Trp-307 Asp311 Trp-613 Trp-616 Asn-617 vdw Ionic bond H-bonds 14 تشرين الثاني، 18

Possible induced dipole dipole interaction between quaternary nitrogen and hydrophobic aromatic rings in binding site N+ induces dipole in aromatic rings d + d - 14 تشرين الثاني، 18

Active conformation of acetylcholine
Several freely rotatable single bonds Large number of possible conformations Active conformation does not necessarily equal the most stable conformation 14 تشرين الثاني، 18

Active conformation of acetylcholine
Rigid Analogues of acetylcholine Rotatable bonds ‘locked’ within ring Restricts number of possible conformations Defines separation of ester and N Muscarinic receptor Nicotinic receptor 14 تشرين الثاني، 18

Instability of acetylcholine
Neighbouring group participation Increases electrophilicity of carbonyl group Increases sensitivity to nucleophiles 14 تشرين الثاني، 18

Requirements Design of cholinergic agonists Correct size
Correct pharmacophore - ester and quaternary nitrogen Increased stability to acid and esterases Increased selectivity 14 تشرين الثاني، 18

Design of cholinergic agonists
Use of steric shields Rationale Shields protect ester from nucleophiles and enzymes Shield size is important Must be large enough to hinder hydrolysis Must be small enough to fit binding site 14 تشرين الثاني، 18

Design of cholinergic agonists
hinders binding to esterases and provides a shield to nucleophilic attack Methacholine asymmetric centre Properties Three times more stable than acetylcholine Increasing the shield size increases stability but decreases activity Selective for muscarinic receptors over nicotinic receptors S-enantiomer is more active than the R-enantiomer Stereochemistry matches muscarine Not used clinically 14 تشرين الثاني، 18

Pharmacologic manipulation of the cholinergic system
Ca2+ Na+ Muscarinic Receptor ACH Choline Acetyltransferase Acetylcholinesterase Acetyl CoA + Acetylcholine Action Potential Choline a b Na+ H+ Nicotinic Receptor ACH Choline Acetate Choline 14 تشرين الثاني، 18 Presynaptic neuron Postsynaptic target

Receptor agonists activate signal transduction pathways
3 NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response C C H 2 C H 2 N C H C H 3 3 O Acetylcholine C H 3 M3 muscarinic receptor 14 تشرين الثاني، 18

Molecular actions of acetylcholine at muscarinic receptors
VI Tyr381 I VII Thr189 V II IV III Asp105 14 تشرين الثاني، 18

ANTICHOLINESTERASES AGENTS Reversible : Short : Edrophonium Medium : Neostigmine, Physostigmine, Pyridostigmine, Tacrine ANS 14 تشرين الثاني، 18

ANS ANTICHOLINESTERASES
14 تشرين الثاني، 18

ANTI-CHOLINESTERASES AGENTS Mechanism of action : Acetyl cholinesterase (AchE) is an enzyme with anionic and esteratic site. Acetylcholine (Ach ) involves attraction of the positive charge N+ of Ach and anionic site; acetylation of serine leading to the acetylated enzyme. The acetylated enzyme reacts with the water to produce acetic acid and free enzyme within milliseconds. ANS 14 تشرين الثاني، 18

CHOLINESTERASES ANS 14 تشرين الثاني، 18

Hydrolysis of acetylcholine by AChE
Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Glu 327 His 440 Phe 338 choline Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Glu 327 His 440 Phe 338 Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Glu 327 His 440 Phe 338 acetate Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Pharmacologic manipulation of AChE: No inhibition
Ca2+ Na+ Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH Action Potential ACH ACH ACH ACH ACH ACH ACH Choline Acetate 14 تشرين الثاني، 18 Presynaptic neuron Postsynaptic target

Pharmacologic manipulation of AChE: Inhibition by drugs
Ca2+ ACH ACH Na+ ACH Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH ACH Action Potential ACH ACH ACH ACH ACH ACH ACH ACH ACH 14 تشرين الثاني، 18 Presynaptic neuron Postsynaptic target

Acetylcholinesterase inhibitors
Tetraalkylammonium ions Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent R CH3 C2H5 C3H7 C4H9 Relative Potency 1.0 5.0 100 50

Quaternary ammonium alcohol Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent

Carbamates Quaternary or tertiary ammonium groups Reversible Covalent modification to AChE Most basic Nitrogen; protonated at physiological pH.

ANS ANTICHOLINESTERASES

Reversible anticholinesterases : Edrophonium, Neostigmine and Physostigmine They combine with the ChE and carbamylated enzyme is slow to hydrolyze and free the enzyme (~30 mins). ANS 14 تشرين الثاني، 18

Inhibition of AChE by Neostigmine

Organophosphates Irreversible Covalent modification to AChE Longer acting Used in the treatment of glaucoma

Organophosphates Nerve gases Irreversible Covalent modification to AChE

Organophosphates Insecticides Irreversible Covalent modification to AChE Rapidly inactivated in mammals

Biotransformation of insecticides
Cyt P450 Insects Carboxyesterase Mammals, Birds

Inhibition of AChE by Organophosphates

Inhibition of AChE by Organophosphates
Aging Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Antidote for AChE “poisoning”
Pralidoxime Chloride (Protopam; 2-pyridine aldoxime methyl chloride; 2-PAM) Antidote for pesticide or nerve gas poisoning Most effective if given within a few hours of exposure

Regeneration of AChE by Pralidoxime

Regeneration of AChE by Pralidoxime
Glu 327 His 440 Phe 338 Anionic site Trp 86 Ser 203 Esteratic site 14 تشرين الثاني، 18

Clinical pharmacology of acetylcholinesterase inhibitors
Type of Route of Drug inhibition administration Clinical Use Edrophonium Rev IM or IV Diagnostic for Myasthenia Gravis Neostigmine Rev IM, IV, or oral Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Physostigmine Rev IM, IV, or local Glaucoma, Alzheimer’s disease, antidote to anticholinergic overdose Tacrine Rev Oral Alzheimer’s disease Donepezil Rev Oral Alzheimer’s disease Isofluorophate Irrev Local Glaucoma Echothiophate Irrev Local Glaucoma 14 تشرين الثاني، 18

Irreversible Anti-cholinesterases: Organophosphorus compounds - Parathion, Malathion The organophosphorus compounds reacts with esteratic site which is hydrolyzed extremely slowly with water or not at all . The phosphorylated enzyme undergo aging by the loss of one of the alkyl groups and become totally resistant to hydrolysis. ANS 14 تشرين الثاني، 18

Synthesis of Ecothiophosphate

CHOLINESTERASE REACTIVATORS : The phosphorylated ChE reacts very slowly or not at all with the water. If more OH groups in the form of Oximes are provided, reactivation occurs faster. Pralidoxime (PAM) attaches to the anionic site in presence of Organophosphorus compounds and set the enzyme free. PAM is ineffective in case of physostigmine poisoning as anionic site is not free. ANS 14 تشرين الثاني، 18

Treatment of Alzheimer’s Disease
Bind to anionic site and block ACh binding Reversible Non-covalent Enhances cognitive ability Does not slow progression of disease Newer agent: Donepezil (Aricept)

Reversible carbamate AChE inhibitor Enhances cognitive ability by increasing cholinergic function Loses effectiveness as disease progresses Side Effects: Nausea, vomiting, anorexia, and weight loss Newer long-acting carbamate: Eptastigmine

Reversible competitive AChE inhibitor Extract from daffodil (Narcissus pseudonarcissus) bulbs Loses effectiveness as disease progresses May be a nicotinic receptor agonist Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability

N-methyl-D-aspartate (NMDA) receptor antagonist NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory Neuronal loss in Alzheimer’s may be related to increased activity of glutamate May slow progression of the disease Favorable adverse effect profile

Thank You! 14 November 2018 4JUNE 2008

Cholinergic Antagonists
By Nohad A AlOmari 14 تشرين الثاني، 18

12. Cholinergic Antagonists (Muscarinic receptor)
Drugs which bind to cholinergic receptor but do not activate it Prevent acetylcholine from binding Opposite clinical effect to agonists - lower activity of acetylcholine Postsynaptic nerve Ach Ach Postsynaptic nerve Antagonist

Clinical Effects Decrease of saliva and gastric secretions Relaxation of smooth muscle Decrease in motility of GIT and urinary tract Dilation of pupils Uses Shutting down digestion for surgery Ophthalmic examinations Relief of peptic ulcers Treatment of Parkinson’s Disease Anticholinesterase poisoning Motion sickness

Thank You! 14 November 2018 4JUNE 2008

12.1 Atropine easily racemised Racemic form of hyoscyamine Source - roots of belladonna (1831) (deadly nightshade) Used as a poison Used as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupils CNS side effects - hallucinations

12.2 Hyoscine (scopolamine) Source - thorn apple Medical use - treatment of motion sickness Used as a truth drug (CNS effects)

12.3 Comparison of atropine with acetylcholine Relative positions of ester and nitrogen similar in both molecules Nitrogen in atropine is ionised Amine and ester are important binding groups (ionic + H-bonds) Aromatic ring of atropine is an extra binding group (vdW) Atropine binds with a different induced fit - no activation Atropine binds more strongly than acetylcholine

12.4 Analogues of atropine Ipratropium (bronchodilator & anti-asthmatic) Atropine methonitrate (lowers GIT motility) Analogues are fully ionised Analogues unable to cross the blood brain barrier No CNS side effects

Cholinergic Antagonists (Muscarinic receptor)
Simplified Analogues Pharmacophore = ester + basic amine + aromatic ring Tridihexethyl bromide Amprotropine Propantheline chloride

Simplified Analogues Benztropine (Parkinsons disease) Tropicamide (opthalmics) Cyclopentolate (opthalmics) Pirenzepine (anti-ulcer) Benzhexol (Parkinsons disease)

12.6 SAR for Antagonists R' = Aromatic or Heteroaromatic Important features Tertiary amine (ionised) or a quaternary nitrogen Aromatic ring Ester N-Alkyl groups (R) can be larger than methyl (unlike agonists) Large branched acyl group R’ = aromatic or heteroaromatic ring Branching of aromatic/heteroaromatic rings is important

SAR for Antagonists Inactive Active

SAR for Antagonists vs. Agonists SAR for Antagonists SAR for Agonists Quaternary nitrogen Aromatic ring Ester N-Alkyl groups = methyl R’ = H Tertiary amine (ionised) or quaternary nitrogen Aromatic ring Ester N-Alkyl groups (R) can be larger than methyl R’ = aromatic or heteroaromatic Branching of Ar rings important

Binding Site for Antagonists RECEPTOR SURFACE Acetylcholine binding site van der Waals binding regions for antagonists

Binding Site for Antagonists

Synthesis of Atropine 14 تشرين الثاني، 18

Cholinergic Drug Lecture 4, 5 &6

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Cholinergic Drug Lecture 4, 5 &6

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