Drugs affecting Cholinergic and Adrenergic receptors

Rule of Thumb on Oxidation

  • In general, in aromatic rings:

    • The position that is electron-rich

    • Has the least steric hindrance

    • This position gets oxidized to form the metabolite.

Structure of the Peripheral Nervous System

  • The nervous system is divided into PNS and CNS. The PNS serves as a communication network that links the CNS to the rest of the body

  • Divisions:

    • Autonomic: Responsible for regulating involuntary bodily functions.

    • Somatic: Controls voluntary movements and is responsible for transmitting sensory information to the CNS and sending motor signals from the CNS to receptors in the skeletal muscles through motor nerves.

  • Autonomic Nervous system:

    • ANS is futher divided into Sympathetic and Parasympathetic Nervous system

    • Sympathetic Nervous System: Prepares the body for 'fight or flight' responses, increasing heart rate, dilating pupils, and inhibiting digestion.

    • Parasympathetic Nervous System: Promotes 'rest and digest' activities, slowing the heart rate, constricting pupils, and stimulating digestive processes.

      • Neurotransmitters:

        • The sympathetic and parasympathetic have receptors in smoth and cardiac muscle.

        • ACh (Acetylcholine) neurotransmitter used to transmit signals in both the sympathetic and parasympathetic nervous systems, playing a crucial role in muscle activation and various autonomic functions.

        • NA (Noradrenaline) used to transmit signals primarily in the sympathetic nervous system, influencing the body's 'fight or flight' responses.

Cholinergic Signaling System

  • Main Effects of Parasympathetic Transmission:

    • Increased tear secretion

    • Eye pupil contraction

    • Increased salivation

    • Decreased heart rate

    • Bronchial contraction

    • Increased gastrointestinal activity

  • Transmitter Used: Acetylcholine

Cholinergic Receptors

  • Types of Cholinergic Receptors:

    • Acetylcholine

    • Nicotine

    • L-(+)-Muscarine

Muscarinic Receptors & Acetylcholine

  • Receptor Types:

    • M1R, M2R, M3R, M4R, M5R

  • Function of Acetylcholine:

    • Acts via different muscarinic receptors for varied physiological effects (e.g., neuromodulation)

Muscarinic Receptor Binding Site

  • Key Features:

    • Hydrophobic pockets involved in binding

    • Specific amino acids and their arrangements are crucial for receptor interaction

Biosynthesis of Acetylcholine

  • Components:

    • Serine

    • Choline

  • Enzymatic Steps:

    • Decarboxylase produces Serine-derived substrates.

    • Acetylation of Choline by Choline Acetyltransferase

Cholinergic Synapse

  • Structure of Synapse:

    • Presynaptic and postsynaptic cells connected via neurotransmitter release

  • Key Steps:

    1. Acetylcholine and choline synthesis

    2. Release and recycling across the synapse

Cholinergic Drugs

  • Types of Cholinergic Drugs:

    • Direct acting: Activate receptors directly

    • Indirect acting: Prevent degradation of acetylcholine, increasing receptor activation.

Direct Acting Cholinergics

  • Applications:

    • Treatment of glaucoma (lowers intraocular pressure)

    • Examples:

      • Pilocarpine

      • Carbachol

      • Acetylcholine eye drops

    • All examples have similar pharmacophore: an ester, alkyl linker and positivly charged amine.

Muscarinic Receptor Binding Sites

  • Key Residues:

    • Trp-307, Asp-311, Trp-613, Trp-616, Asn-617, etc.

  • Significance:

    • Influence on receptor activation by ligands.

Structure-Activity Relationships (SAR) for Cholinergics

  • Factors Affecting Activity:

    • Correct distance between nitrogen and oxygen in structure

    • Placement of small alkyl groups close to functional groups

Indirect Acting Cholinergics

  • Function:

    • Inhibit acetylcholinesterase enzyme, preventing acetylcholine degradation.

  • Uses:

    • Myasthenia gravis

    • Alzheimer's Disease

Acetylcholinesterase Structural Features

  • Key Amino Acids Involved:

    • Histidine, Serine, Glutamic acid

  • Mechanism of Action:

    • Interaction with acetylcholine and subsequent hydrolysis.

Acetylcholinesterase Mechanism

  • Role of Catalysts:

    • Serine acts as a nucleophile attacking the carbonyl carbon of the acetylcholine, facilitating the cleavage of the ester bond and leading to the formation of choline and acetate.

    • Histidine acts as both base and acid in this catalytic triad mechanism.

Anticholinesterases - Mechanism and Application

  • Anticholinesterases inhibit the activity of acetylcholinesterase.

  • Natural Products:

    • Neostigmine, Pyridostigmine

  • Mechanism:

    • Carbamoyl group transfer to Ser200 in active sites

Anticholinesterases Structural Characteristics

  • Serine residue in anticholinesterases acts as a nucleophile and attacks physostigmine while a histidine residue acts as both base and acid in this catalysis.

  • A stable carbamoyl intermediate will form leading to slow hydrolysis.

Anticholinesterases in CNS

  • Importance:

    • Attain efficacy in diseases like Alzheimer's Disease

  • Example: Rivastigmine.

Irreversible Acetylcholinesterase Inhibitors

  • Examples:

    • Organophosphorus compounds (e.g., Sarin, Tabun)

  • Mechanism:

    • Bind irreversibly to active site serine residues of acetylcholinesterase, preventing degradation of acetylcholine.

Antidotes to Organophosphate Poisoning

  • Example: Pralidoxime (Pro-2-PAM iodide)

  • Action:

    • Reverses the phosphorylation of serine residues in acetylcholinesterase.

Anticholinergic Drugs

  • Function:

    • Block acetylcholine action at muscarinic receptors (G-protein-coupled receptors)

  • Effects:

    • Eye pupil dilation, decreased salivation, decreased GI secretion.

Natural Products as Anticholinergics

  • Major natural sources:

    • Hyoscyamus niger, Atropa belladonna, Datura stramonium

Semisynthetic Anticholinergics

  • Compounds like Methylscopolamine and Ipratropium for specific therapeutic actions.

Synthetic Anticholinergics

  • All have an aromatc ring connected with a ring and an ester linkage leadning to an ionised amine.

  • Function:

    • Provide spasmolytic effects.

Synthetic Anticholinergics for Urologic Use

  • Examples like Emepron and Tolterodine

  • Use:

    • Treat urologic spasm.

CNS Targeting Synthetic Anticholinergics

  • Used for treating Parkinson's disease

  • Compounds must pass blood-brain barrier.

Synthesis of Acetylcholinesterase Inhibitors

  • Learn the different synthetic tools used for organic synthesis

Synthesis of Anticholinergics

  • Learn the different synthetic tools used for organic synthesis

The Adrenergic Nervous System

  • Also known as the sympathetic nervous system

    • Uses a variety of neurotransmitters, including norepinephrine and epinephrine, to mediate the body's fight or flight response.

  • Results:

    • Sympathetic effects like increased heart rate and relaxation of smooth muscles.

Page 35: Adrenergic Receptors

  • Types:

    • Alpha and Beta receptors

  • General:

    • Agonism at alpha-receptors → contraction noradrenaline > adrenaline > isoprenaline

    • Agonism at beta-receptors → relaxation

      isoprenaline >> adrenaline > noradrenaline

  • Response Type:

    • Varies with agonism and hormone interaction (e.g., norepinephrine and adrenaline).

Alpha Receptors

  • Types: Alpha1 and Alpha2

  • Function:

    • Alpha1: Smooth muscles contraction, such as in blood vessels and pupils.

    • Alpha2: Inhibition of neurotransmitter release, leading to decreased sympathetic outflow and reduced blood pressure.

Mechanism of Alpha Receptors

  • Alpha1 Mechanism:

    • Gq pathway causing calcium release - contributing to muscle contraction.

    • Causes pupillary dialation, vasoconstriction etc.

Beta Receptors and Mechanisms

  • Receptor Types:

    • Beta1, Beta2, and Beta3

    • Increases cAMP

  • General Function:

    • Beta 1: Inceases heart rate and renin release in kidneys

    • Beta 2: Enhance airflow in lungs and smooth muscle relaxation

    • Beta 3: Stimulates breakdown of fat in dipose tissue

Biosynthesis of Noradrenaline

  • Learn the different synthetic tools used for organic synthesis

  • Process:

    • Tyrosine → Levodopa → Dopamine → Noradrenaline.

Synthesis, release and regulation of Norepinephrine

  • Tyrosine is the precursor for NE synthesis, which is first converted to DOPA and then dopamine in the nerve terminal. Dopamine is then converted to NE in synaptic vesicles.

  • NE is released upon nerve stimulation in the synaptic cleft (space between the nerve terminal and the target cell) and binds to receptors on the target cell to exert its effects.

  • NE action is regulated by reuptake mechanisms and feedback inhibition.

  • Certain drugs, like cocaine, interfere with NE reuptake, enhancing its action.This leads to increased levels of NE in the synaptic cleft, resulting in heightened physiological responses such as elevated heart rate and increased blood pressure.

Inactivation of Norepinephrine

  • By inhibiting the reuptake of NE to the nerve terminal, the action of NE is inactivated.

  • Methabolic pathways involving COMT and MAO-A.

Adrenergics - Sympatomimetics

  • Direct acting adrenergic agonists bind directly to adrenergic receptors, mimicking the effects of neurotransmitters like norepinephrine and epinephrine.

  • Indirect acting adrenergic agonists, on the other hand, enhance the release of norepinephrine from nerve terminals or inhibit its reuptake, thereby increasing its availability at the receptor sites.

Alpha-Receptor Agonists Structure

  • Alpha-agonists: (R)-noradrenaline, (R)-adrealine, dipivephrine.

    • Usually two hydroxyl groups ortho to each other on aromatic ring

  • Alpha1-aginists: (R)-phenylephrine, (R)-norphenephrine

    • Usually one hydroxyl group on aromatic ring

Beta-Receptor Agonists Structure

  • Unselective beta1/beta2-agonists: (R)-adrenaline, isoprenaline, orciprenaline

    • Usually two hydroxyl groups ortho to each other on aromatic ring

  • Selective beta1-agonists: erilephrine

    • Usually one hydroxyl group on aromatic ring

Synthetic Beta2-Receptor Agonists

  • Examples like Salbutamol and Formoterol for treating asthma.

Structure-Activity Relationships (SAR) of Adrenergics

  • The presence of a bulky side chain enhances selectivity for beta-receptors, while small side chain enhances selectivity for alfa-receptors.

  • Only primary or secondary amine

  • R-enatiomer most active

  • Removal of OH group ortho to the other OH group on aromatic ring enhances selectivity for alpha1/beta1 receptors

  • Presence of OH group meta to the other OH group enhances selectivity towards beta 2 receptors

Stabilization of Catecholamines

  • Catecholamines are important neurotransmitters that play a crucial role in the body's response to stress, regulating heart rate, blood pressure, and glucose metabolism.

    • Examples dopamine, norepinephrine and epinephrie

  • Catecholamines are easily oxidized

    • Prevent oxidation by addition of sodium pyrosulphite or EDTA

Antiadrenergics Overview

  • First generation beta-receptor blockers.

    • partially agonists

    • Unselective beta1/beta3-receptor blockers

  • Second generation beta-receptor blockers.

    • good antagonists

    • Unselective beta1/beta3-receptor blockers

  • Third generation beta-receptor blockers.

    • Provides selective blockade of beta-1 receptors, minimizing side effects on beta-2 receptors and enhancing therapeutic efficacy.

SAR antiadrenergics

  • S-enatiomer most active

  • Only secondary amines

  • Bulky side chains

  • Aromatic system is necessery

  • Ether directly linked to the aromatic system is often present but not necessary

Synthesis of Antiadrenergics

  • Learn the different synthetic tools used for organic synthesis

Synthesis of beta-receptor blockers

  • Learn the different synthetic tools used for organic synthesis

Key Topics to Remember

  • The structures of acetylcholine, noradrenaline and adrenaline

  • The difference between direct and indirect acting cholinergics

  • SAR cholinergics

  • SAR acetylcholinesterase inhibitors

  • Irreversibel inhibitors of acetylcholinesterase - pralidoxime antidote

  • SAR anticholinergics

  • Synthesis of drugs acting at cholinergic receptors or at acetylcholinesterase

  • The difference between direct and indirect acting adrenergics

  • SAR adrenergics (alpha-receptor selective vs beta-receptor selective)

  • SAR antiadrenergics

  • Synthesis of drugs acting at adrenergic receptors.