Introduction To Autonomic Nervous System PDF

Medicinal Chemistry I – (PC 504) 3rd Year 5th Semester Introduction to autonomic nervous system Prepared by Shrouk Mahmoud  Enzymes as drug targets Many important drugs act as enzyme inhibitors. In other words, they hinder or prevent enzym...

Medicinal Chemistry I – (PC 504) 3rd Year 5th Semester Introduction to autonomic nervous system Prepared by Shrouk Mahmoud  Enzymes as drug targets Many important drugs act as enzyme inhibitors. In other words, they hinder or prevent enzymes acting as catalysts for a particular reaction. The binding interactions holding the substrate or the product to the enzyme must be properly balanced. They must be sufficiently strong to hold the substrate in the active site long enough for the reaction to occur, but weak enough to allow the product to leave. There are several types of enzyme inhibitors: 1- Reversible inhibitors 2- Irreversible inhibitors 3- Allosteric site inhibitors 1- Competitive Reversible inhibitors: - Competitive inhibitors bind to the active site through intermolecular bonds and so the binding is reversible, allowing an equilibrium to occur between bound drug and unbound drug. - This means that the inhibition caused by the drug is reversible. If the concentration of substrate increases, it competes more effectively with the drug for the active site, and so inhibition by the drug will be less effective. - The inhibitor is likely be similar to substrate, product or cofactor. 2- Irreversible inhibitors: - Irreversible enzyme inhibitors can form a covalent bond to a key amino acid in the active site and permanently block the affected enzyme. For examples: Penicillin, proton pump inhibitors and orlistat. - Irreversible enzyme inhibitors are not competitive inhibitors. Increasing the concentration of substrate will not reverse their inhibition as the inhibitors cannot be displaced from the active site.  Receptors as drug targets - A receptor is a protein molecule within the cell membrane with part of its structure facing the outside of the cell. embedded - The protein surface will be a complicated shape containing hollows, ravines, and ridges, and in this complicated geography, there will be an area which has the correct shape to accept the incoming messenger. This area is known as the binding site and is analogous to the active site of an enzyme. When the chemical messenger fits into this site, it 'switches on' the receptor molecule and a message is received. However, there is an important difference between enzymes and receptors: the chemical messenger does not undergo a chemical reaction. It fits into the binding site of the receptor protein, passes on its message and then leaves it unchanged. Binding of a messenger to a receptor.  When the chemical messenger fits into this site it ‘switches on’ the receptor molecule and a message is received The binding site of a receptor changes shape when a chemical messenger fits into it. Both the messenger and the binding site take up different conformations or shapes to maximize the bonding forces between them. It is this overall shape change that is crucial to the activation of a receptor and in its ability to trigger an amazing ‘domino effect’ which affects the cell’s internal chemistry. There are three different types (or families) of membrane-bound receptors: ion channel receptors; G-protein-coupled receptors; kinase-linked receptors. The drug act on receptor may be 1- Agonist It is a drug that mimic the natural chemical messengers and interacts with the receptor in the same way. 2- Antagonist It is a drug that will bind to the binding site, but will not activate the receptor. Since it is bound, it will prevent the normal ligand from binding and activating the receptor. 3- Partial agonist The compound acts as an agonist and produces a biological effect, but that effect is not as great as one would get with a full agonist.so it cannot be defined either as a pure antagonist or a pure agonist The partial agonist may be capable of distinguishing between different receptor types or subtypes, acting as an agonist at one subtype, but as an antagonist at another subtype.  illustrative example (only for reading) Estrogen receptor (ER) undergoes extensive conformational changes after ligand binding. The conformation of the ER ligand-binding domain is determined by the nature of the particular ligand that is bound. In the estrogen-liganded complex, helix 12 within the ER ligand-binding domain is repositioned over the ligand-binding cavity to form a secure lid over the ligand. This ER conformation exposes several amino acids that are critical for binding to specific coactivator proteins. In contrast, the repositioning of helix 12 over the ligand-binding cavity is prevented by tamoxifen or raloxifene Ligand binding domain is shown in gray with the C-terminal H12 helix colored yellow, estradiol and tamoxifen are colored green short helical peptide (colored brown), which is derived from the TIF2 transcriptional co-activator  Theory for drug receptor interaction 1.Ariens And Stephenson Theory Introduced Terms of "affinity" & "efficacy Affinity is the ability of the drug to combine with receptor to produce a drug receptor complex. Intrinsic activity or efficacy is the ability of drug-receptor complex to initiate a response. According to this theory: Agonist is a drug with a high affinity and a high intrinsic activity. Partial agonist is a drug with a favorable affinity and a low intrinsic activity. Antagonist is a drug with a high affinity and no intrinsic activity. Drugs acting on Autonomic nervous system  Acetylcholine is the chemical transmitter for nerves of the parasympathetic, somatic, preganglionic sympathetic, and parts of CNS There are 2 types of cholinergic receptors Muscarinic Nicotinic Muscarine is the Nicotine is the prototypical prototypical muscarinic nicotinic agonist agonist located primarily at effector located in autonomic organs such as eye, heart, ganglia and GIT, urinary tract, neuromuscular junction. exocrine glands. G protein–coupled ligand- gated ion channel receptors could be either which modulate passage of excitatory (M1,M3,M5) or ions, principally K+ and Na+, inhibitory (M2,M4) through the channel. 1. Biosynthesis of Acetylcholine (ACh). 1 2. Storage of ACh. 3. Release of ACh. 2 4. Binding of ACh. to the receptor. 5. Degradation of ACh. 6. Recycling of choline 3 6 5 4 Cholinergic effects Diarrhea mediated by M3 (inc. motility, inc. secretion) Urination mediated by M3 (contraction of bladder) M1 (excitatory) in CNS M2 (inhibitory) in heart Miosis M3 pupil contraction, lens elongation M3 (excitatory) in exocrine Bronchoconstriction M3 in airways (inc. secretion, constriction) glands, eye, lung, GI, bladder Bradycardia M2 cardiac muscle (dec. Heart rate) Excitation M1 in brain Lacrimation M3 in lacrimal gland Salivation M1 and M3 in salivary gland Sweating M in sweat gland  The structure of acetylcholine could be divided into three components; the cationic (quaternary ammonium head), the ethylene bridge and the acetoxy function. The positively charged nitrogen together with the carbonyl oxygen have an electron withdrawing effect. Water is poor nucleophile, but since the carbonyl group is now more electrophilic hydrolysis takes place easily.This influence of nitrogen atom is known as neighboring group participation. neighboring group participation Why acetylcholine could not be given as a drug? Rapid hydrolysis of acetylcholine in the stomach by acid catalysis, so it cannot be given orally. Rapid hydrolysis of acetylcholine in the blood both chemically and enzymatically by AChE, so it cannot be given parenterally. There is no selectivity of action, it exhibits both muscarinic and nicotinic effects. Cholinergic drugs are developed to Mimic the actions of ACh at the postsynaptic receptor (agonists) Block the enzymatic hydrolysis of ACh (AchE inhibitors) Block the actions of ACh at the postsynaptic receptor (antagonists) Cholinergic drugs are useful in Alzheimer’s disease Myasthenia gravis Stimulate smooth muscle of GIT after surgery Treatment of glaucoma (by enhancing the outflow of aqueous humor thereby reducing intraocular pressure) Binding interactions at muscarinic receptor A. The anionic site: responsible for the electrostatic interaction between the positive charge of the quaternary nitrogen and a negative charge at this site originating from a carboxylate ion of the free carboxyl group of dicarboxylic amino acid (e.g., aspartate or glutamate). B.The esteratic site: which involves a hydrogen bond between the ester oxygen of acetylcholine and hydrogen present at this site (from asparagine amino acid).  Number between nitrogen and terminal hydrogen is fie atoms Ester group is essential for activity Quaternary nitrogen or 3ry amine gp is essential for optimal activity Ethylene bridge is essential for Acetyl group is optimal for activity size of R agonist activity activity Increasing the length decreases Me2 Et or Me2, propyl less active If methyl is replaced by activity Et3 antagonist NH2 (carbamate derivative) α-methyl gp nicotinic activity hydrolysis lead to longer ß-methyl gp muscarinic activity duration  Design of acetylcholine analogs the fit between acetylcholine and its receptor is so tight that there is little scope for enlarging the molecule. Steric shield Electronic effect Both steric and electronic Methacholine Carbachol (can be Bethanechol Diagnostic for asthma administered orally) Orally active (methacholine challenge test), ttt of glaucoma ttt of urinary retention Varenicline is partial where asthmatics will react to nicotinic agonist and was lower doses of drug. approved as an aid to stop smoking The α-methyl analog is nicotinic agonist Mechanism of Ach hydrolysis by AchE enzyme Inactive acylated enzyme  Inactive acylated enzyme Regenerated enzyme Acetylcholine hydrolysis Inactive acylated enzyme Regenerated active enzyme Regeneration of active Acetylcholine esterase enzyme i- Reversible Anticholinesterases (Acetylcholinesterase Inhibitors, AChEIs) Clinically useful AChEIs include the aryl carbamates Carbamic acid (i.e. esters of carbamic acid and phenols). When aryl carbamate AChEIs bind to the catalytic site of AChE, hydrolysis of carbamate occurs leading to carbamylated enzyme. The rate of hydrolytic regeneration of the carbamylated enzyme is measured in minutes while in case of acetylated AChE is measured in milliseconds The carbamylated-enzyme intermediate is stabilized as nitrogen can feed a lone pair of electrons into the carbonyl carbon. Regeneration of active AChE by hydrolysis of the carbamylated enzyme is much slower than hydrolysis of the acetylated enzyme. Used orally for the treatment of myasthenia gravis Myasthenia gravis is an autoimmune disease where the body destroys the nicotinic receptors on muscle, leading to muscle weakness and fatigue. Inhibiting the hydrolysis of acetylcholine allows a greater activation of remaining receptors.