Organic Pharmaceutical Chemistry II Lecture 1 - University of Al-Ameed PDF

University of Al-Ameed College of Pharmacy Organic Pharmaceutical Chemistry I I 4th class/ 1st semester lecture 1 CHOLINERGIC AGENTS; CHOLINERGIC RECEPTORS AND THEIR SUBTYPES Dr. Abbas Abdulridha Overview of Nervous System...

University of Al-Ameed College of Pharmacy Organic Pharmaceutical Chemistry I I 4th class/ 1st semester lecture 1 CHOLINERGIC AGENTS; CHOLINERGIC RECEPTORS AND THEIR SUBTYPES Dr. Abbas Abdulridha Overview of Nervous System 2 Adrenergic and cholinergic innervations in sympathetic and parasympathetic nervous systems 3  Introduction Cholinergic nervous system refer to the part of Nervous system that utilize Acetylcholine (Ach) as a neurotransmitter. Cholinergic nerves are found in the peripheral nervous system and central nervous system (CNS) of humans. Its presence in the CNS is currently receiving the most attention, as researchers are beginning to unlock the mysteries surrounding cognitive impairment and, most particularly, Alzheimer disease. Synaptic terminals in the cerebral cortex, corpus striatum, hippocampus, and several other regions in the CNS are rich in ACh and in the enzymes that synthesize and hydrolyze this neurotransmitter. Many experiments show that agonists and antagonists of cholinergic receptors can modify the output of neurotransmitters, including ACh, from brain preparations. Although the function of ACh in the brain and brain stem is not clear, it has been implicated in memory and behavioral activity in humans. 4 5 The peripheral nervous system consists of those nerves outside the cerebrospinal axis and includes: ▪ the somatic nerves and ▪ the autonomic nervous system. The somatic nerves are made up of a sensory (afferent) nerve and a motor (efferent) nerve. The motor nerves arise from the spinal cord and project uninterrupted throughout the body to all skeletal muscle. ACh mediates transmission of impulses from the motor nerve to skeletal muscle (i.e., neuromuscular junction). The autonomic nervous system is composed of two divisions: sympathetic and parasympathetic. ACh serves as a neurotransmitter at both sympathetic and parasympathetic preganglionic nerve endings, postganglionic nerve fibers in the parasympathetic division, and some postganglionic fibers (e.g., salivary and sweat glands) in the sympathetic division of the autonomic nervous system. The autonomic nervous system regulates the activities of smooth muscle and glandular secretions. These, as a rule, function below the level of consciousness (e.g., respiration, circulation, digestion, body temperature, metabolism). ✓ The two divisions have contrasting effects on the internal environment of the body: The sympathetic division frequently discharges as a unit, especially during conditions of rage or fright, and expends energy. The parasympathetic division is organized for discrete and localized discharge and stores and conserves energy. Neurotransmitters (NT): chemical messengers or Neurotransmitters (NT): are endogenous chemicals that transmit signals across a synapse from sending presynaptic neuron to the target postsynaptic neuron. They are synthesized and stored in neuron itself. There are many NTs eg: Acetylcholine, Adrenaline, serotonin, dopamine, GABA The very fact that neurotransmitters are chemicals allows the medicinal chemist to design and synthesize organic compounds which can mimic ( agonists ) or block (antagonists) their action.  The cholinergic signaling system Let us look first at what happens at synapses involving acetylcholine as the neurotransmitter. These figures shows the synapse between two neurons and the events involved when a message is transmitted from one neuron to another. The same general process takes place when a message is passed from a neuron to a muscle cell. Presynaptic control systems Cholinergic receptors (called autoreceptors ) are present at the terminus of the presynaptic neuron. The purpose of these receptors is to provide a means of local control over nerve transmission. When acetylcholine is released from the neuron, some of it will find its way to these autoreceptors and switch them on → Leading to inhibiting further release of acetylcholine. The presynaptic neuron also contains receptors for noradrenaline , which act as another control system for acetylcholine release. Biosynthesis of Acetylcholine ✓ ACh is prepared in the nerve ending by the transfer of an acetyl group from acetyl-coenzyme A (CoA) to choline. ✓ The reaction is catalyzed by ChAT. ✓ Choline is the limiting substrate for the synthesis of ACh. ✓ Most choline for ACh synthesis comes from the hydrolysis of ACh in the synapse. Biosynthesis of Acetylcholine Biosynthesis of Acetylcholine ethanolamine Acetyl Co-A choline 14 Hypothetical model of synthesis, storage, and release of ACh  Cholinergic neurons synthesize, store, and release ACh. The neurons also form choline acetyltransferase (ChAT) and AChE. AChE is also located outside the neuron and is associated with the neuroglial cells in the synaptic cleft. 1. ACh is released from storage granules under the influence of the nerve action potential and Ca+2. 2. ACh acts on postsynaptic cholinergic receptors. 3. Hydrolysis of ACh by AChE occurs in the synaptic cleft. 4. A high-affinity uptake system returns choline to the cytosol. 5. ChAT synthesizes ACh in the cytosol, and the ACh is stored in granules. 6. Glucose is converted to pyruvate, which is converted to acetyl-CoA in the mitochondria. Acetyl-CoA is released from the mitochondria by an acetyl carrier. ?? 7. Choline is also taken up into the neuron by a low-affinity uptake system and converted partly to phosphorylcholine. ✓ Choline is recaptured by the presynaptic terminal as part of a high-affinity uptake system under the influence of sodium ions to synthesize ACh. Q/ Several quaternary ammonium bases such as Hemicholinium (HC-3) and the triethyl analog of choline, 2-hydroxyethyltriethylammonium, cause a delayed paralysis at repetitively activated cholinergic synapses and can produce respiratory paralysis in test animals? These compounds act as competitive inhibitors of choline uptake. The delayed block is caused by the depletion of stored ACh, which may be reversed by choline. Q/ After ACh has been released into the synaptic cleft, its concentration decreases rapidly, Explain briefly. It is generally accepted that there is enough AChE at nerve endings to hydrolyze into (choline and acetate) any ACh that has been liberated. Metabolism of acetylcholine 19 Cholinergic receptors There are two distinct receptor types for ACh that differ in composition, location, and pharmacological function and have specific agonists and antagonists. Cholinergic receptors have been characterized as: nicotinic and muscarinic on the basis of their ability to be bound by the naturally occurring alkaloids nicotine and muscarine, respectively. Receptor subtypes that differ in location and specificity to agonists and antagonists have been identified for both the nicotinic and muscarinic receptors. 1. Nicotinic Receptors Each α-chain contains a negatively charged binding site for the quaternary ammonium group of ACh. The receptor appears to exist as a dimer of the two five-subunit polypeptide chain monomers linked through a disulfide bond between chains. Nicotinic receptors are coupled directly to ion channels and, when activated by Ach, mediate very rapid responses.  When the neurotransmitter ACh binds to the nicotinic receptor, it causes a change in the permeability of the membrane to allow passage of small cations Ca+2 , Na , and K. The physiological effect is to temporarily depolarize the end plate. This depolarization results in : muscular contraction at a neuromuscular junction or, as occurs in autonomic ganglia, continuation of the nerve impulse. Neuromuscular nicotinic ACh receptors are of interest as targets for autoimmune antibodies in myasthenia gravis and for muscle relaxants used during the course of surgical procedures. Nicotinic receptors in autonomic ganglia, when blocked by drugs, can play a role in the control of hypertension. HOW?  Factors affecting selectivity of ion pores include both: The charge of the ion and The size of the ion. Ions in aqueous solution are hydrated. The water around the ion is characterized by the presence of two distinct water structures: A tightly bound, highly ordered layer immediately surrounding the ion and A second, less structured layer. Ion transport through a channel requires some denuding of the surrounding water shell. The degree of organization of the water structure determines the energy required to remove the hydration shell and is a factor in the selectivity of that ion channel. Hydrated cation showing a highly structured shell of water around the cation (A), a less struc tured layer surrounding the inner water shell (B), and water in a “normal” state (C). NICOTINIC RECEPTOR SUBTYPES Nicotinic receptors located in the neuromuscular junction differ from those on neurons, such as those in the CNS and autonomic ganglia, in that → they have different ligand specificities. 1. Nicotinic receptors at the neuromuscular junction (N1) are blocked by succinylcholine, d-tubocurarine, and decamethonium and stimulated by phenyltrimethylammonium. 2. N2-nicotinic receptors are found in autonomic ganglia. They are blocked by hexamethonium and trimethaphan but stimulated by tetramethylammonium and dimethyl-4 phenylpiperazinium (DMPP).  2. Muscarinic receptors These receptors have seven protein helixes that transcend the plasma membrane, creating four extracellular domains and four intracellular domains. The extracellular domain of the receptor contains the binding site for ACh. The intracellular domain couples with G proteins to initiate biochemical changes that result in pharmacological action from receptor activation. Muscarinic receptors mediate their effects by activating guanosine triphosphate (GTP)-binding proteins (G proteins). Muscarinic receptors play an essential role in regulating the functions of organs innervated by the autonomic nervous system to maintain homeostasis of the organism. The action of ACh on muscarinic receptors can result in stimulation or inhibition of the organ system affected. ACh stimulates secretions from salivary and sweat glands, secretions and contraction of the gut, and constriction of the airways of the respiratory tract. It inhibits contraction of the heart and relaxes smooth muscle of blood vessels. Muscarinic receptor subtypes and functions 29 Physico-chemical property of Ach Prototype muscarinic and nicotinic agonist It is a short-acting miotic when introduced into the anterior chamber of the eye. It cannot be administered topically, because it is not lipophilic enough to penetrate the cornea. In the presence of acid or base, as in GIT, the rate of hydrolysis is so fast that it prevents oral dosing of Ach. Can not be administered as IV dosage form because it will be degraded by a hydrolyzing enzyme called butrylcholinesterase in plasma. 30 What makes acetylcholine exceptionally prone to hydrolysis? Due to the possibility of folding to form an intramolecular dipole bond that will increase the positive charge of the ester carbonyl and makes that carbon atom electron deficient and more prone to nucleophilic attack. Water is a poor nucleophile, but, because the carbonyl group is more electrophilic, hydrolysis takes place relatively easily. Neighboring group participation. The arrow indicates the inductive pull of oxygen which increases the electrophilicity of the carbonyl carbon. If there is a lack of acetylcholine acting at a certain part of the body, why not just administer more acetylcholine? After all, it is easy enough to make in the laboratory. There are three reasons why this is not feasible: 1. Acetylcholine is easily hydrolyzed in the stomach by acid catalysis and cannot be given orally. 2. Acetylcholine is easily hydrolyzed in the blood by esterase enzymes (esterases). 3. There is no selectivity of action. Additional acetylcholine will switch on all cholinergic receptors in the body. Ach synthesised in laboratory easily Cholinergic Agent the drugs and chemicals that act on cholinergic nerves or the tissues they innervate to either mimic or block the action of ACh. Drugs that mimic the action of ACh do so either by acting directly on the cholinergic receptors in the tissue or by inhibiting acetyl cholinesterase (AChE), the enzyme that inactivates ACh at the nerve terminal. Chemicals that bind or compete with ACh for binding to the receptor may block cholinergic neurotransmission. 33 Tackling the inherent instability of acetylcholine There are two possible approaches to tackling the inherent instability of acetylcholine: Steric shields and Electronic stabilization. 1. Steric shields can be demonstrated with methacholine Here, an extra methyl group has been placed on the ethylene bridge as a steric shield to protect the carbonyl group. The shield hinders the approach of any potential nucleophile and also hinders binding to esterase enzymes, thus slowing down chemical and enzymatic hydrolysis. As a result, methacholine is three times more stable to hydrolysis than acetylcholine.  why not put on a big ger alkyl group like an ethyl group or a propyl group? Alternatively, why not put a bulky group on the acyl half of the molecule, as this would be closer to the carbonyl centre and have a greater shielding effect? Introducing a methyl steric shield has another useful effect. It was discovered that methacholine has significant muscarinic activity, but very little nicotinic activity. 2. Electronic effects can be demonstrated with carbachol The use of electronic factors to stabilize functional groups was used in the design of carbachol (a long-acting cholinergic agent) which is resistant to hydrolysis. Here, the acyl methyl group has been replaced by NH2 which means that the ester has been replaced by a urethane or carbamate group. This functional group is more resistant to hydrolysis because the lone pair of electrons on nitrogen can interact with the neighboring carbonyl group and lower its electrophilic character. ✓ Although the NH2 group is equivalent in size to the methyl group, the former is polar and the latter is hydrophobic, and it was by no means certain that a polar NH2 group would be accepted into a hydrophobic pocket in the binding site ? ✓ Fortunately, the activity is retained, which means that the amino group acts as a bioisostere for the methyl group. A bioisostere is a group which Thus, the amino group is a bioisostere can replace another group for the methyl group as far as the without affecting the cholinergic receptor is concerned pharmacological activity of but not as far as the esterase enzymes are interest concerned. The inclusion of the electron-donating amino group greatly increases chemical and enzymatic stability. Unfortunately, carbachol shows very little selectivity between the muscarinic and nicotinic receptors. → Nevertheless, it is used clinically for the treatment of glaucoma, How we can avoiding the problems of receptor selectivity? Glaucoma arises when the aqueous contents of the eye cannot be drained. This raises the pressure on the eye and can lead to blindness. Agonists cause the eye muscles to contract and allow drainage, thus relieving the pressure. It can be applied locally, thus avoiding the problems of receptor selectivity. 3. Combining steric and electronic can be demonstrated with bethanechol effects Bethanechol resulting by adding a β-methyl group to carbachol a compound which is both stable to hydrolysis and selective in its action. It is occasionally used therapeutically in stimulating the GIT and urinary bladder after surgery. H.W ACh can binds to two main types of receptors: nicotinic and muscarinic. Explain briefly.