Adrenergic and cholinergic agents

This presentation contains a brief introduction of Adrenergic and cholinergic systems and their function in our body.
And a brief description of some adrenergic and cholinergic agents along with their mechanism of action along with their respective Structures.

1. Presentation on advanced Medicinal chemistry-1 TOPIC-ADRENERGIC AND CHOLINERGIC AGENTS Presented by Tapas Majumder M.PHARMA, 1 st SEM Enrollment no-2106240007 Dept. of pharmacy Tripura University(a central university) Presented to Dr. Kuntal Manna Associate professor Dept. of pharmacy Tripura University(a central university)

2. CONTENTS Introduction to Adrenergic system and receptors. Introduction to Adrenergic agents(agonist and antagonist) classification, Mechanism of action, SAR and Synthesis of few molecules. Introduction to Cholinergic system and receptors. Introduction to Cholinergic agents(agonist and antagonist) classification, Mechanism of action, SAR and synthesis of few molecules. References 2

3. Adrenergic system and receptors The adrenergic system or adrenergic nervous system is a group of organs and nerves in which adrenaline, noradrenaline and Dopamine act as neurotransmitters. These are 3 closely related endogenous catecholamines(CAs). ANS is counted as one of the main neurohormonal systems that regulate cardiovascular function including smooth muscle. Noradrenaline -It acts as transmitter at postganglionic sympathetic sites (except sweat glands ,hair follicles and some vasodilator fibres) and in certain areas of brain. Adrenaline- It is secreted by adrenal medulla and may have a transmitter role in brain. Dopamine -It is a major transmitter in basal ganglia ,limbic system, CTZ, anterior pituitary etc and in a limited manner in the periphery. 3

4. 4 Biosynthesis of catecholamines

5. RECEPTORS Adrenergic receptors are membrane bound G- protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers c-AMP OR IP3/DAG. In some cases the activated G-protein itself operates K + or Ca 2+ channels or increases prostaglandin production. Adrenergic receptors are classified into two ALPHA( α ) and BETA( β ). Alpha and beta receptors further divided into α 1, α 2, β 1, β 2,β3. 5 Adrenergic Receptors:

6. 6 Receptor type Tissue location α 1 Arterioles(coronary, visceral, cutaneous), Veins, internal sphincters, Iris sphincter. α 2 Presynaptic membrane, pancreas, veins, adipose tissue, Salivary glands. β 1 Heart(SA node, arterial muscle, Av node, ventricles),Kidney(JG apparatus),Adipose tissue. β 2 Arterioles(muscular), veins, bronchi(muscles),Liver, pancreas, uterus, iris constrictor muscle. β 3 Adipose tissue, Urinary bladder.

7. Adrenergic Agent DEFINITION: Adrenergic agents also properly called adreno mimetics or adrenergic stimulant and improperly known as Sympathomimetics are drugs that produce affects which are similar to the response from stimulation of adrenergic nerves. Adrenergic drugs act on effector cells through adrenoreceptors that normally are activated by neurotransmitter norepinephrine or they may act on neurons that release the neurotransmitter. These drugs are used in many life-threatening conditions ,including cardiac arrest ,shock, asthma attack or allergic reaction. 7

8. SYMPATHOMIMITICS: Direct acting: These drugs act directly on or more adrenergic receptors. According to their receptor selectivity they are two types NONSELECTIVE - ADRENALINE(almost all adrenergic receptors, treatment cardiac arrest, anaphylaxis) NORADRENALINE(acts on α1 , α 2, β 3, treatment of shock and hypotension) ISOPRENALINE(acts on β1, β 2, β 3, treatment of bradycardia and heart block) SELECTIVE: drugs which act on a single receptor only. α1selective-OXYMETAZOLINE(decongestant) α2selective-CLONIDINE(hypertension and ADHD) β1selective-DOBUTAMINE(treatment of cardiogenic shock) β 2selective-SALBUTAMOL,(in the treatment of Asthma),TERBUTALINE. 8

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10. 10 Mechanism: Mechanism: Activation of α 1 receptors initiates a series of reactions through the G- protein activation of phospholipase c ,ultimately resulting in the generation of second messengers inositol-1,4,5-triphosphate (IP3) and Diacyl-glycerol( DAG).IP3 initiates the release of Ca 2+ from the endoplasmic reticula, into the cytosol, and DAG turns on other proteins within the cell. Thus ,tissues with a predominance of β 2 receptors (such as vasculature of skeletal muscle) are particularly responsive to the effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the 3 types of β receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell.

11. INDIRECT ACTING: These are the substance that enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the neurotransmitter receptor itself. They work at the nerve terminal to promote the release and block the reuptake and degradation of endogenous neurotransmitter because they are indirect acting agonists ,these drugs have little activity if these neurotransmitters are depleted. EXAMPLE- EPHEDRINE,COCAINE,AMPHETAMINE USE- used to treat breathing problems (broncho dialator ),nasal decongestant, low bp. 11

12. Structure –ACTIVITY RELATIONSHIP Phenyl ring substitution: The naturally occurring nor-adrenaline has 3-4 dihydroxy benzene ring (catechol)active at both α and β - receptors but it has poor oral activity because it is rapidly metabolized by COMT(catecholamine O-methyl transferase).Change in substitution pattern to3-5-dihydroxy as in metaproterenol gives oral activity to metabolism by COMT it also provides selectivity for β 2 receptor. 3-hydroxy substitution is required for α 1 activity. 12

13. Substitution at Nitrogen: The receptor selectivity is dependent upon the size of alkyl group present on Nitrogen. As the size is increased from hydrogen in Nor-adrenaline to methyl in adrenaline to isopropyl in Isoproterenol, activity of α - receptors decreased and β - receptor activity increased. Substitution of carbon in site chain (R2): An ethyl group at the position diminished α - activity. There are 2 carbon atoms α and β to nitrogen, small alkyl groups methyl or ethyl increases duration of action and make the compound is resistant to metabolic deamination by MAO. 13

14. 14 SYNTHESIS OF SALBUTAMOL

15. SYMPATHOLYTICS: Definition: A sympatholytic drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system. They are also used to treat anxiety, such as generalized anxiety disorder ,panic disorder. They also known as anti-adrenergic. 15 CLASSES OF SYMPATHOLYTIC: α-ADRENERGIC BLOCKERS: Non-selective α blocker: T hey are antagonists at both alpha1 and alpha 2 receptors TOLAZOLINE (used in the treatment of RAYNAUD’s disease) ,PHENTOLAMINE (used to reverse numbness after oral and dental procedures), PHENOXYBENZAMINE. Selective α blocker: Selectively blocks the subtypes of alpha subunits( α 1b and α 1 d) and gives vasodilation effect. Apart from that these increases HDL and decreases LDL. Agents-PRAZOSIN,TERAZOSIN AND DOXAZOSIN.

16. β -ADRENERGIC BLOCKER: class of drugs which prevent the stimulation of the adrenergic receptors( β1, β 2, β 3) responsible for increased cardiac action, used to control heart rhythm, treat angina and reduce high blood pressure. Propranolol one of the potent beta blocker also used in the following conditions-Hyperthyroidism, prophylaxis of migraine, anxiety with somatic presentation. Example – PROPRANOLOL,ATENOLOL,BISOPROLOL,ESMOLOL,CARVEDILOL(blocks both β + α 1) 16

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18. Structure activity relationship 18 By replacing 2 –OH group on benzene ring in Isoproterenol with Chlorine atom gives di chloroproterenol which is having partial agonistic activity .

19. By substituting the Catechol nucleous with Napthalene ring ,gives a prominent compound called Pronethelol . 19 By substituting aryl group with heterocyclic rings Indole, thiadiazole give Pindolol and Timolol. By substituting aryl group with P-substituted phenyl moiety makes the compound selective for β -antagonist. R= ACETAMIDE-Atenolol AMIDE- Acebutalol Ester-Esmolol Ether- Metaprolol

20. 20 Synthesis of Propranolol

21. CHOLINERGIC SYSTEM

22. Introduction to cholinergic system Definition : The cholinergic system is composed of organised nerve cells that use the neurotransmitter ACETYLCHOLINE in the transduction of action potentials. These nerve cells are activated by or contain and release acetylcholine during the propagation of a nerve impulse. The cholinergic system has been associated with a number of cognitive functions ,including memory, selective attention and emotional processing. 22

23. Cholinergic transmission Synthesis, storage and destruction of Acetylcholine: Acetylcholine is synthesized in the presynaptic neuron from 2 substances ACETYL –CoA and choline, with the help of enzyme Choline acetyltransferase(CAT). Acetyl CoA is produced by metabolism of glucose and fat in our body, where as we are dependant on exogenous source for choline as it can not be synthesized. Choline is also recycled from the synapse after breakdown of acetylcholine in the synapse and this being the most important source of choline ,is the rate limiting step in acetylcholine synthesis. After synthesis ,acetylcholine enters into a vesicle by H+-Ach ATPase. The vesicle has a protein attached called SVP(synaptic vesicular protein). Once the action potential strikes the presynaptic membrane, it is depolarized ,and this results in opening of CALCIUM channels. Rise in intramolecular calcium stimulates vesicle movement until it fuses with presynaptic membrane and acetylcholine outpoured into the synaptic cleft. 23

24. The duration of acetylcholine action in the synaptic cleft is only for milliseconds, as it is immediately metabolized by ACHE(Acetyl choline Esterase) into choline and acetate . Choline is recycled into presynaptic neuron for synthesis of acetylcholine and this is the rate limiting step of acetylcholine synthesis. 24

25. Cholinergic receptor Introduction: The receptors in cholinergic system are two types ,MUSCARINIC (M) AND NICOTINIC(N). Nicotinic receptors are ligand gated Na+ ion channels ,whereas muscarinic receptors are GPCRs. NICOTINIC RECEPTOR: Nicotinic receptors are pentameric structures made up of 4 protein subunits (2 α ,1 β ,1 ε and 1 δ ). There are 2 sites of binding of acetylcholine on α subunit ,which opens the ion channel and conducts Na+ and Ca +2 into the cells causing depolarisation. It has 2 subunits(muscular Nm and Neuronal Nn ). Location- The Nn subtypes are located in the adrenal medulla depolarize the cells, Nn receptors in the ganglions generate action potential that is propagated in the postganglionic axons, Nn receptors in CNS cause stimulation (arousal and attention) and analgesia. Nm- found in neuromuscular junction and leads muscle contraction. 25

26. Muscarinic receptors: Muscarinic receptors are of five subtypes and all GPCRs. The odd ones are M1,M3,M5 are Gq subtypes , which on stimulation increases calcium. The even ones M2,M4 are Gi subtypes and on stimulation decrease cyclic AMP and open K+ channels .Overall M3 subtype has the widest distribution and is most common Muscarinic receptor. Thus, the odd ones are present ,they will produce an effect corresponding to increase in calcium and the even ones will produce an effect corresponding to decrease in cyclic AMP and opening of K+ channels which relaxation. 26

27. Parasympathomimetic: also known as cholinomimetic or cholinergic receptor stimulating ,is a substance that stimulates the parasympathetic nervous system . These chemicals are also called cholinergic drugs because acetylcholine (Ach) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the Nicotinic or muscarinic receptors (thus mimicking acetylcholine )or indirectly by inhibiting Cholinesterase ,promoting acetylcholine release. Common uses of para sympathomimetics include Glaucoma, Underactive bladder. Some chemical weapons such as Sarin or VX ,non-lethal riot control agents such as tear gas and insecticides such as diazinon fall into this category. AGENTS: Direct acting parasympathomimetic : They act by stimulating the nicotinic or muscarinic receptors. CHOLINE ESTERS : ACETYLCHOLINE(all acetylcholine receptors, used as Myotic to reduce postoperative rise in Intra ocular pressure associated with Cataract surgery) ),BETHANECHOL(M3 receptors),METHACHOLINE(all muscarinic receptors, used in eye drops as a Myotic for diagnostic purpose) CHOLINOMIMETIC ALKALOID : PILOCARPINE(M3 receptors ,used in the treatment of Glaucoma (mainly open angle Glaucoma),dry eyes and dry mouth) 27

28. INDIRECT ACTING PARASYMPATHOMIMETIC: Indirect acting parasympathomimetic substances may be either reversible cholinesterase inhibitors, irreversible cholinesterase inhibitors which inhibit the hydrolysis of Ach by the AChE (acetylcholinesterase) produce their cholinomimetic effects indirectly. REVERSIBLE CHOLINESTERASE INHIBITOR: PHYSOSTIGMINE(used in the treatment of atropine or belladonna poisoning and also used in Glaucoma),NEOSTIGMINE(Used in the treatment of abdominal distention and paralytic ileus-temporary paralysis of intestinal muscle that helps in the movement of food through intestine ),EDROPHONIUM(used in the diagnosis of Myasthenia gravis). IRREVERSIBLE CHOLINESTERASE INHIBITOR: also known as organophosphates. Insesticides -PARATHION,MALATHION. Therapeutic -ECHOTHIOPATE(used in the treatment of Glaucoma) CHOLINEESTERASE REACTIVATOR: PRALIDOXIME 28

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30. MECHANISM OF INDIRECT ACTING AGENTS: Acetylcholine structure consists of 2 important moiety such as Cationic group and ester group. Correspondingly Acetyl cholinesterase has 2 active site that are involved in the binding and cleavage of Acetyl choline , they are cation binding site and Ester site.. CATION BINDING SITE: Cation binding site is made up of Glutamate having Carboxylate anion hence negative in charge. Therefore it attracts + ve ly charged Quartarnary ammonium group of the acetyl choline. ESTER BINDING SITE: It is also known as Esterate site is responsible for cleavage of Acetyl choline at Ester group leads into formation of Choline and Acetate .This site is made up of Serine having Hydroxyl (-OH) can interact with Ester group. This hydroxyl group can interact with Ester group in Acetyl choline by hydrogen binding . Many of the anti-cholinesterase bind to both sites there by incubates its activity by Organo phosphates mainly bind to Ester site with no action on Cationic binding site. 30

31. MECHANISM OF ACTION OF CHOLINESTESE REACTIVATOR : PRALIDOXIME is mainly used here. It is used as an antidote for poisoning by pesticides. Pralidoxime used at a dose of 1-2 mg over less than 5 min. These compounds bind to the anionic site and remove the phosphate group from the esteratic site thereby dephosphorylating and activating ACHE. 31

32. Structure activity relationship 32 1 .Modification of Quaternary Ammonium Group : The quaternary ammonium group is essential for intrinsic activity and contributes to the affinity of the molecule for the receptors ,partially through the binding energy and partially because of its action as a detecting group. The Trimethyl ammonium group is the optimal functional moiety for the activity ,although some exceptions are known(pilocarpine, Nicotine) and it shows maximal muscarinic activity.

33. Placement of primary, secondary or Tertiary amines leads to decrease in activity. 2. Modification of acetoxy group: The ester group of Ach contributes to the binding of the compound to the muscarinic receptor. Replacement of methyl group by ethyl or large alkyl groups produces inactive compounds. Esters of aromatic or higher molecular weight acids possess cholinergic antagonist activity. 3.Modification of ethylene bridge: The methyl ester is rapidly hydrolysed by cholinesterase to choline and acetic acid .To reduce susceptibility to hydrolysis ,carbamate esters of choline (Carbachol) were synthesized and were found to be more stable than carboxylate esters. Placement of α-substitution in choline moiety results in a reduction of both Nicotinic and Muscarinic activity,but Muscarinic activity to a greater extent. Incorporation of β- substitution leads to reduction of Nicotinic activity to grater extent. Replacement of ester group with Ether or Ketone produces chemically stable and potent compounds. 33

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35. PARASYMPATHOLYTIC AGENTS: The agents which selectively reduce or abolish the affects of para-sympathetic stimulation ,are known as para-sympatholytic agents or anti cholinergic or cholinergic antagonist. These include Atropine and related alkaloids obtained from plants such as Atropa belladonna, Atropa accuminata , Hyoscyamus niger , Datura stramonium and synthetic or semisynthetic Atropine substituents. These drug block the Muscarinic actions of Acetyl choline but the ganglionic and skeletal neuromuscular actions of Acetyl choline are not affected. 35

36. ATROPINE( IV/IM in range of 0.01-0.02 mg/kg upto adult dose of 0.4-0.6mg) Use- as anti spasmodic -given in patients of bronchial asthma, as mydriatic As anti secretory- pre-anesthetic medication: reduces excessive salivation and respiratory secretions. SCOPOLAMINE( 0.3-0.5 mg I/M ) Use- prevent Nausea and vomiting caused by motion sickness or from anesthesia given during surgery). MECHANISM OF ANTICHOLINERGICS: Anticholinergics are the drugs that block the neurotransmitter ACETYLCHOLINE in CNS and PNS. These drugs combine reversibly with Muscarinic receptors thus preventing access of neurotransmitter acetylcholine in these sites. 36

37. Structure activity relationship 37 For potent cholinergic antagonist the groups R1 and R2 must be hydrophobic in nature. In the general structure for Amino alcohol the substituent R1 and R2 should be Carboxylic or heterocyclic ring for max. antagonistic activity. The R3 group can be Hydrogen, Hydroxyl, hydroxymethyl, Amide or a component of the R1 and R2 group. Best potency is seen with hydroxyl or hydroxymethyl(this hints that the oxygen group must be participating in H bond. The X is mostly ester in most potent derivatives but it can be a ether oxygen or absent completely. The N substituent can be bot Quaternary ammonium salt or tertiary amine with different alkyl groups. Most potent derivatives have Quaternary ammonium salt. The alkyl group is not restricted to only methyl ,it can be propyl or isopropyl. The distance between ring substituted carbon and Nitrogen is not fixed but maximum potency requires about 2 carbon units.

38. 38 SYNTHESIS OF ATROPINE SYNTHESIS OF PROCYCIDINE HYDROCHLORIDE

39. References Lippincott Illustrated Reviews:Pharmacolgy,7 th edition page no 3-293 Conceptual review of Pharmacology by Dr.Ranjan kumar patel 4 th edtion,CBS publishers and distributors ltd.85-103 Previous notes. Wikipedia. https://www.slideshare.net/ParasuramanParasuraman/autonomic-nervous-system-122037114 https://www.slideshare.net/ParasuramanParasuraman/adrenergic-system https://www.healthline.com/health/adrenergic-drugs https://www.ncbi.nlm.nih.gov/books/NBK534230/ https://www.researchgate.net/publication/340646500_Sympathomimetics_and_Sympatholytics_SAR_Classification_Biosynthesis_of_Adrenaline_by_PROFESSOR_BEUBENZ https://youtu.be/wZdtIcTFz80 https://youtu.be/dYmZj4zjjc0 https://youtu.be/2RcXUxx0HzM https://youtu.be/41Xloc_vvX8 https://youtu.be/cp_CZpCBVpk 39

40. 40 http://www.pharmacy180.com/article/structural-activity-relationship-2211/ https://link.springer.com/referenceworkentry/10.1007%2F978-0-387-79948-3_1113 https://www.slideshare.net/DrVishalKandhway/anticholinergic-drugs-51899813 https://www.slideshare.net/SagarJoshi2/antispamodics-med-chem-lecture https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389556/ https://tmedweb.tulane.edu/pharmwiki/doku.php/prazosin . http://www.gmch.gov.in/sites/default/files/documents/Adrenoceptor-activating-&-other-sympathomimetic-drugs-Copy2.pdf.

41. 41 THANK YOU