Drugs Affecting The Autonomic Nervous System Fall 2024 PDF

Drugs Affecting The Autonomic Nervous System Fall 2024 Farghaly A. Omar (Ph. D) Professor of Medicinal Chemistry Autonomic Nervous System involves: 1) The parasympathetic Sector: Acetylcholine is the neurotransmitter in preganglionic and postganglionic nerves (Cholinergic s...

Drugs Affecting The Autonomic Nervous System Fall 2024 Farghaly A. Omar (Ph. D) Professor of Medicinal Chemistry Autonomic Nervous System involves: 1) The parasympathetic Sector: Acetylcholine is the neurotransmitter in preganglionic and postganglionic nerves (Cholinergic sector). 2) The sympathetic Sector : Norepinephrine (mainly) and epinephrine (in adrenal gland) are the neurotransmitters at the postganglionic sites (Adrenergic sector). Functionally, the two are generally antagonistic. The sympathetic division stimulates functions involved in “fight or flight” reactions (fear, anger, etc), Whereas the parasympathetic division stimulates more tranquil functions (“rest-and-digest”).  Parasympathetic drugs Learning Objectives 1. Discuss the role of acetylcholine (ACh) as a neurotransmitter including its biochemistry (i.e., biosynthesis, stereochemistry, storage, and metabolism). 2. Identify the cholinergic receptors, compare the muscarinic versus the nicotinic receptors. 3. Recognize the mechanism of action of cholinergic drugs. (Agonist – Antagonist – Directly & Indirectly acting – Muscarinic & Nicotinic) 4. List the structure–activity relationships (SARs) of cholinergic drugs.. 5. Discuss the pharmacokinetic aspects of the cholinergic drugs & their clinical application. Parasympathetic Drugs: 1.1 Agonists at the cholinergic receptors: Parasympathomimetics, Cholinomimetics Choline esters & related drugs; Cholinesterase inhibitors. 1.2 Antagonists: Parasympatholytics, anticholinergics. 1) Acetylcholine 2-(Acetyloxy)-N,N,N-trimethylethanaminium chloride. An ester of choline alcohol and acetic acid. Choline is an amino alcohol & exist as quaternary ammonium salt. Acetylcholine is the endogenous neurotransmitter at both preganglionic and postganglionic parasympathetic nerve endings. Biosynthesis of acetylcholine Chemical Synthesis of choline esters: R R HCl + (CH3)3N HOCHCH2N(CH3)3 Cl O O R (CH3CO)2O N(CH3)3 Cl H3C O Parasympathetic Receptors Two main types are known: 1) Muscarinic Receptors (mAChR): ❑ Distributed in CNS & peripheral tissues. ❑ Consists of seven hydrophobic transmembrane (TM) helical domains. ❑ Subtypes (M1 to M5). Model of muscarinic receptor  Muscarinic receptor binding site. A tight fit between ACh and its binding site, which leaves little scope for variation. 2) Nicotine Receptors (nAChRs) ❑ Location in skeletal muscle neuromuscular (NM) junction, adrenal medulla, and autonomic ganglia. ❑ Classified as ligand-gated ion channel receptors. The nAChR creates a transmembrane ion channel where ACh serves as a gate-keeper by binding with the nAChR to modulate passage of ions (i.e., K+, Na+). Model of Nicotinic receptor Molecular Characteristics of Ach: Stereochemical Aspects: The molecule can exist in different conformational orientations (How?) Bond rotations in Ach Leading to different conformations. Studies have shown that the orientation of the ester group and the quaternary nitrogen is important for binding, and that the distance differs for the muscarinic and the nicotinic receptor. Guache conformer Anti- conformer Therapeutic significance: 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 ❑ Acetylcholine is a poor therapeutic agent? Very low chemical stability? Poor bioavailability after oral or parenteral administration?? Nonselective: interact with all cholinergic receptors. CH3 The chemical instability of Ach: H3C CH3 The positively charged N has EW effect and N attracts the negatively charged oxygen δ O of the carbonyl group. The carbonyl C-atom becomes electron H3C δ O deficient and more prone to nucleophilic attack. Molecular modifications to attain: Chemical stability Receptor selectivity Steric hindrance Methacholine electronic stabilization Carbachol Bethanechol ?  2) Acetylcholine analogues O CH3 The steric effect: H3C O N(CH3)3 * 2.1 Methacholine The methyl group build in a shield for the carbonyl oxygen and hinder the electrostatic interaction with the positively charged nitrogen. Chemical stability Methacholine is sufficiently stable to attain sustained parasympathetic stimulation at the muscarinic receptors. Chiral center (R) & (S) isomers. Muscarinic selectivity resides principally in the (S) isomer. The electronic effect: Replacement of the CH3 group by NH2 afford the carbamate group (the lone pair of electrons on the nitrogen diminish the electrophilic character of the carbonyl group by resonance and resists hydrolysis. 2.2 Carbachol is nonspecific in its action on muscarinic receptors. It is equipotent to Ach but has longer duration. 2.3 Bethanechol is the most chemically more stable than Ach?. can be used orally. O O CH3 N(CH3)3 N(CH3)3 H2N O H2N O * b) Carbachol c) Bethanechol SAR Essential features Acetoxy Quaternary ammonium group group O CH3 + – H3C O CH2 CH2 N CH3 Cl Ethylene CH3 group Higher alkyl (Less active) Aromatic (Antagonist) NH2COO (Carbachol long acting) Ether or ketone (long acting) 3) Noncholine derivatives Natural or synthetic compounds that act directly on the cholinergic receptors. Their therapeutic applications involves: Treatment and diagnosis of glaucoma (miotic action). Management of Alzheimer’s disease. 3.1) Muscarinic agonists a) Pilocarpine hydrochloride [Assign the essential features] Alkaloid obtained from Pilocarpus jaborandi. Ophthalmic solution used as the miotic of choice for open-angle glaucoma. The lactone is susceptible to chemical hydrolysis to the inactive pilocarpic acid. It should be properly stored. Epimerization of the ethyl side chain in alkaline pH to the inactive epimer.  Although there is no quaternary ammonium group present in pilocarpine, it is assumed that the drug is protonated before it interacts with the muscarinic receptor. Molecular modelling shows that pilocarpine can adopt a conformation having the correct pharmacophore for the muscarine receptor; i.e. a separation between nitrogen and oxygen of 4.4 A. b) Xanomeline M1/M4 agonist. Not tolerated orally, but used transdermally for management of AD Oxathiolane ring O c) CEVIMELINE HCl S Selective M3 receptors Quinuclidine ring esp. in lacrimal & salivary gland epithelia 1/2 H2O N Administered orally used for xerostomia Cl (mouth dryness) H 4) Indirectly acting cholinomimetics Acetylcholinesterase Inhibitors (AChEIs), i.e. interfere with the mechanism by which the action of Ach is terminated. This leads to accumulation of Ach and prolongation of its action. Enzyme inhibition may be reversible or irreversible. Therapeutic applications: - Improvement of muscle strength in myasthenia gravis. - In open angle glaucoma to decrease intraocular pressure. - Management of Alzheimer’s disease. 1) Reversible AChEIs *1) Physostigmine An alkaloid. The lead compd. for AChEIs. Structural features: Carbamate group is essential for activity; Benzene ring involved in some extra hydrophobic bonding. Pyrrolidine nitrogen is important and is ionized at physiological pH. It binds to the anionic binding region of the enzyme. Therapeutic uses: - Treatment of glaucoma. - Treatment of CNS toxicity with some anticholinergic drugs. - Treatment of Alzheimer’s disease.  It undergoes hydrolytic decomposition in aqueous solution leading to loss of the carbamoyl moiety and the resulted phenol subjected to light-catalysed oxidation to rubreserine which is inactive. HO H3C Eseroline N N CH3 CH3 O H3C O N N CH3 CH3 rubreserine 2) Neostigmine bromide 3) Pyridostigmine Br- O N(CH3)2 O N(CH3)2 O O N N(CH3)3 Br CH3 Br 3-[(dimethylcarbamoyl)oxy]-N,N,N-trimethylanilinium bromide. Synthetic reversible AChEIs; substituted carbamate, benzene ring, and the quat. nitrogen atom. The distance between the ester group and the quaternary ammonium group is approximately the same as that found in Ach. Quat. Nitrogen minimize the CNS side effects. They are orally active and used in the treatment of myasthenia gravis. Synthesis of Neostigmine: AChEIs for management of Alzheimer’s Disease 1) Rivastigmine (Exelon): CH3 It is a centrally acting. H3C O CH3 N CH3 Inhibits AChE for up to 10 hours N CH3 O (pseudo-irreversible AChEI) 2) Donepezil (Aricept®): A nonclassical centrally acting reversible, non- competitative AChEI. (Allosteric binding) It has greater affinity for H3CO AChEIs in the brain. H3CO N O  b) Irreversible AChEIs Mostly are organophosphate esters. Used as nerve poisons in warfare and as insecticides. The irreversible inhibition of AChE? results in accumulation of Ach at nerve endings and exacerbate Ach-like actions. General Formula: R1 = Alkoxy group A R2 = alkoxy, alkyl, or tertiary amine X = a good leaving group (e.g. F, CN, R1 P X thiomalate, p-nitropheny) R2 A = O; S; Se (In case of S and Se it should be bioactivated to the oxo form).  H3CO O O P H3CO O H3CO S O P O H3CO OH O O Ser-200 Ser-200 Echothiophate A long acting antiglaucoma drug resulting in a decrease of intraocular pressure for about one week or more. Its use is limited to patients, resistant to other antiglaucoma agents. Treatment of Organophosphate poisoning: 1) Anticholinergic agents N 2) Pralidoxime chloride: Cl N OH Cholinestrase regenerator CH3 H 2-formyl-1-methylpyridinium chloride oxime. 2-PAM: pyridine aldoxime methyl chloride It is not one of the cholinergic drugs but is used as antidote for organophosphate poisoning.  Activation of Cholinesterases by PAM H3CO O O P H3CO O H3CO S O P O H3CO OH O O Ser-200 Ser-200 The hydroxylamine is a strong nucleophile 2-PAM H CH3 N N H3CO O OH P H3CO OH O Ser-200 Ser-200  2.1) Muscarinic antagonists Include many natural and synthetic compounds: 1) Solanceous alkaloids: Atropine and its semisynthetic derivatives. 2) Synthetic compounds: aminoalcohols; esters; and aminoamides. Therapeutic uses: Antispasmodics: Teatment of organophosphate poisoning. Relief of peptic ulcers. Ophthalmic examination: Dilation of eye pupils. Parkinson’s disease. Surgical operations: Reduction of saliva and gastric secretions.  CH3 1) Atropine: N Naturally occurring alkaloid. H Ester of tropic acid & tropine CH2OH O alcohol. Contains chiral center * in the tropic acid moiety. O - Rationale for antagonistic effect: easily racemized - A basic nitrogen - An ester group - The distance between the two groups is similar to that in Ach. - But the bulky aryl residues result in receptor blocking. 1) Atropine derivatives: Mostly are quaternary salts of atropine for ophthalmic use only. The quaternization of the nitrogen atom enhance their polarity and consequently reduces the central side effects relative to atropine. Acetylcholine and atropine superimposed skeletons. Homatropine methyl bromide Mandelic acid ester. Rapid onset and short mydriatic Minimal CNS side effects.  Tiotropium Tiotropium is a long-acting, antimuscarinic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD) and asthma. Tiotropium acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation and bronchodilation. 2) Aminoalcohol esters: 2.1) Propantheline Bromide 2.2) Cyclopentolate HCl Spasmolytic (intestinal mydriatic drug for eye examination hypermotility). 3) Aminoalcohol Ethers: Their therapeutic uses are mainly as antiparkinsonial agents. Benztropine: 3-Diphenylmethoxytropane. CH O N CH3 It combines anticholinergic; antihistaminc and local anesthetic properties. Used as long acting antiparkinsonial agent? It exerts a sedative effect; therefore, it used as bedtime medication. SAR of muscarinic antagonists: For maximum activity, should be Carbocyclic or heterocyclic rings. The rings may be identical, most compounds have different rings. R1 R2 N OH > CH2OH > H; NH2CO; or CONH2 X R3 Quat. N or tert. that Ester COO > Ether -O- can be protonated. the substituents: CH3; C2H5; or C3H7 Nicotinic Antagonists The nicotinic antagonists fall into two subclasses: The ganglionic blocking agents and The neuromuscular (NM) blocking agents. NM blocking agents represents the therapeutically useful drugs. The first drug known is d-tubocurarine, a muscle- paralyzing agent. The NM blocking agents are competitive antagonists of nicotinic receptors. Pharmacophore Two quaternary ammonium centres at specific separation. Different binding interactions. The tubocurarine molecule bridges two acetylcholine binding sites within the one protein complex. The therapeutic uses of neuromuscular blocking agents is as an adjunct to general anesthesia. They produce skeletal muscle relaxation that facilitates operative procedures. A. Nondepolarizing Competitive Ganglionic Blockers. 1) Hexamethonium + 5 3 1 Muscle relaxant in surgical N + N operations. 6 4 2 2) Pentolinium It works by binding to the + 5 3 1 N + acetylcholine receptor of N 6 4 2 adrenergic nerves, resulting in inhibition of the release of noradrenaline and adrenaline. Hence, smooth muscle relaxation and vasodilatation. Given orally, or parenterally. It can be used as an antihypertensive drug during surgery or to control hypertensive crises CH3 B. Depolarizing Ganglionic Blockers. O N CH3 1) Suxamethonium (Succinyl choline): O CH3 It represents two molecules of Ach O CH3 N connected at the α-carbon to the CH3 O CH3 carbonyl group. Short duration (5 min.) due to rapidly hydrolysis in aqueous solution and by plasma esterases. It is a depolarizing neuromuscular blocking agent.  MeO OMe O O Me H 2) Atracurium MeO N CH 2 CH 2 C O (CH 2)5 O C CH 2 CH 2 N OMe OMe MeO OMe OMe Design based on tubocurarine and suxamethonium Lacks cardiac side effects Rapidly broken down in blood both chemically and metabolically Lifetime is 30 minutes Administered as an i.v. drip  Sympathetic Drugs Agents affecting adrenergic neurotransmission. Therap. Applications in a variety of clinical conditions, including cardiovascular, and asthma. 1.1 Endogenous (Adrenergic Neurotransmitters) Norepinephrine NE; (R = H) H OH H Epinephrine EP; (R = CH3) HO N R HO NEP: R-(-)-α-(Aminomethyl)-3,4-dihydroxybenzyl alcohol EP: R-(-)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl Alcohol Adrenergic receptors: Found throughout the peripheral and central sympathetic nervous systems and belong to the family of G-protein–coupled receptors (GPCRs). Broadly classified as α or β receptors depending on the affinity of N-substituted analogs of NE. ❑ α1-Receptors are predominantly postsynaptic and found in vascular smooth muscle and the CNS. ❑ α2-Receptors (autoreceptors) are predominantly presynaptic. Their action regulates the release of NE from storage vesicles. Stimulation inhibits adenylcyclase, which decreases intracellular cyclic adenosine monophosphate (cAMP) and inhibits the release. ❑ β1-Receptors are primarily located in the myocardial. Stimulation results in increased chronotropic (heart rate) and inotropic (force of contraction) effects. ❑ β2-Receptors are found in lungs, uterus, vascular smooth muscle, and skeletal muscle. Stimulation results in relaxation or dilation of these tissues. Β-receptor subtypes are also found in the CNS. ❑ β3-Receptors are located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Some β3 agonists have demonstrated antistress effects in animal studies, suggesting it also has a role in the central nervous system (CNS). β3 receptors are found in the gallbladder, urinary bladder, and in brown adipose tissue. Beta adrenergic receptors are involved in epinephrine- and norepinephrine-induced activation of adenylate cyclase through the action of the G proteins (type Gs). Drug targets affecting noradrenaline transmission 1. The enzymes involved in the biosynthesis of Noradrenaline. 2. The vesicle carriers which package noradrenaline within the presynaptic neuron prior to release. 3. The process of releasing noradrenaline: vesicles fuse with the cell membrane 4. Adrenergic receptors in the postsynaptic neuron. 5. The transport proteins which are responsible for the reuptake of noradrenaline from the synaptic gap 6. The metabolic enzymes which metabolize noradrenaline. 7. The presynaptic adrenergic receptors which regulate noradrenaline release.  Biosynthesis of Epinephrine NH2 HO NH2 Rate limiting COOH COOH HO Tyrosine HO hydroxylase Tyrosine Dopa decarboxylase OH HO NH2 Dopamine HO NH2 B-hydroxylase HO HO Dopamine NEP N-methyltransferase OH HO NHCH3 N.B. Enzyme inhibitors as therap. agents HO Adrenergic binding site. Comparison of α- and β-adrenoceptor binding sites. Two important Points regarding adrenergic receptors Interactions: The structural difference between α and β receptors. The stereochemical aspects of the ligands. 1.2 Sympathomimetics “Adrenergics” Classes: 1. Directly Acting Adrenergics Direct interaction with the (Adrenergic Agonists) adrenergic receptors 1.1 Endogenous A. Phenethylamines 1.2 Synthetic analogs B. Imidazolines -Agonists; -Agonists C. Guanidines 2. Indirectly acting sympathomimetics: Action due to release of NE from adrenergic nerve terminals. 3. Mixed acting sympathomimetics : interact partially with adrenergic receptors and cause release of NE. [Have no OH on the aromatic ring; have β-OH group on side chain] 1. Directly Acting Sympathomimetics H OH HO H A. Phenethylamines N R Norepinephrine NE; (R = H) HO Epinephrine EP; (R = CH3) Due to the presence of phenolic and amino functions they are amphoteric at physiological pH (7.4). They exist as: 93% protonated amine; 3% zwitter ion 4% nonionized c.f. receptor interactions? H OH O NH2R H O All are catecholamines, are very susceptible to air oxidation to give o-quinones, which undergo further reactions to give colored products (adrenochromes). They should be stabilized by antioxidants. General methods of Assay: Adrenochrome 1) Non aqueous titration: Basic FG. Using perchloric acid (Vs) (crystal violet as indicator). 2) Spectrophotometrically (colorimetric method): H OH Colored chelate with Fe(II) salt, H O N which is measured Fe CH3 spectrophotometrically at 550 nm. O Uses: 1) EP: Vasoconstrictor in cases of hemorrhage. Prolong the duration of action of local anesthetics. For open angle glaucoma. 2) NEP: vasoconstrictor in acute hypotension status. Derivatives: 1. Epinephrine borate (sod. Salt): used as buffered solution (pH 7.4) Releases EP on dissociation. 2. Dipivaloyl epinephrine: Eye drops converted by esterases in the eye to epinephrine. Used as antiglaucoma. 1.Directly Acting Adrenergics OH 6 H 5 1 N Assign the structural requirements * R1 R3 for selectivity in each class: 2 R2 4 3 Drug R1 R2 R3 a) Nonselective ,  activity I- Endogenous: Norepinephrine H H 3,4-di-(OH) Epinephrine CH3 H 3,4-di-(OH) b) Selective -Agonists (Synthetic) Phenylephrine CH3 H 3-OH Metaraminol H CH3 3-OH Methoxamine H CH3 2,5-di-(OCH3) c) -Agonists (mainly 2) OH 6 H 5 1 N * R1 R3 2 R2 4 3 R1 R2 R3 Isoproterenol CH(CH3)2 H 3,4-di-(OH) bronch. asthma Isoetherine CH(CH3)2 Et 3,4-di-(OH) -”- Metaproterenol CH(CH3)2 H 3,5-di-(OH) -”- Colterol C(CH3)3 H 3,4-di-(OH) -”- Terbutaline C(CH3)3 H 3,5-di-(OH) -”- Albuterol C(CH3)3 H 3-CH2OH, 4-OH -”- Structure–activity relationships (SAR) of catecholamines.  Stereochemical Aspects EP & NEP posses a chiral carbon, exist as enantiomers. The R-(-) configuration is the natural isomer and the biologicaly active. Ser 204 Ser 204 O O H Ser 267 H Ser 267 O O O H O H H H O H O H H H H HO Phe H Phe H O H NH3 H NH3 COO COO Asp 113 Asp 113 R-(-) form Three points attachment S-(+)form two points Adrenergic binding site. Selective α-Adrenergic Agonists: 2. Arylimidazoles 2.1) Naphazoline modified PEA structure. Vasoconstrictors Lipophilic substituent / limited CNS effect? ionized at pH = 7.4 (pKa = 9 – 10) 2.2 Clonidine Hydrochloride 2,6-dichloro-N-(imidazolidin-2-yl)aniline Centrally acting α2-adrenoreceptors in the CNS. Used as antihypertensive agent? Unionized at physiological pH? The dichlorophenyl substituent reduces the basicity of the guanidine moiety (pKa = 13.6) to be 8.0. Enhanced lipophilicity -. Synthesis of Clonidine 3. β-Agonists: OH H Selective β2-agonists HO N 3.1) Terbutaline Bronchodilators with minimal cardiovascular actions. Longer duration. OH Synthesis of Terbutaline 3.2) Albuterol (Salbutamol) OH H N Anti-asthmatic drug. HO In cases of COPD. It has the same potency as HO isoprenaline but is 2000 times less active on the heart. The R enantiomer is 68 times more active than the S enantiomer. SAR: Replacement of the m-CH2OH groups that capable of H- bonding with the receptor e.g.: MeSO2NHCH2 , HCONHCH2, H2NCONHCH2, retains the activity. EWG on the ring have poor activity (e.g. COOH). Bulky meta substituents are bad for activity because they prevent the substituent adopting the necessary conformation for hydrogen bonding; The CH2OH group can be extended to CH2CH2OH but no further. B3-adrenergic receptor agonists: 1) Mirabegron 2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino} ethyl)phenyl]acetamide Mirabegron is used is in the treatment of overactive bladder. Beta-3 adrenergic agonists activate brown adipose tissue (BAT) and increase energy expenditure, leading to research interest in their development as weight loss drugs. 2) Solabegron Acts as a selective agonist for the β3 adrenergic receptor. Treatment of overactive bladder and irritable bowel syndrome. It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes.  Adrenergic antagonists Sympatholytics include α- and β-adrenergic antagonists. α-antagonists are generally vasodilators and expected to be used as antihypertensive agents. 1) Nonselective α-Antagonists Antagonists block the action of released NEP and circulating EP on postsynaptic α1-receptors. 1.2) Phentolamine It is a reversible nonselective α-adrenergic antagonist. For the control of hypertensive emergencies, most notably due to pheochromocytoma?. Synthesis: Alkylation of 3-(4-methylanilino)phenol using 2-chloro- methylimidazoline 2) α1-Selective Antagonists 2.1) Selective α1A-receptors antagonists: Therapeutic agents for benign prostatic hyperplasia (BPH). Tamsulosin and Silodosin are used exclusively for this indication. Tamsulosin is a benzene-sulfonamides and silodosin is an indoline-7-carboxamide. Silodosin is the more selective α1A-selective agent, leading to fewer cardiovascular adverse effects. Tamsulosin Silodosin 2.2) Selective α1B-Antagonists (Azosins) Antihypertensive agents Consisting of 4-amino-6,7-dimethoxyquinazolines. Prazosin is used exclusively in hypertension. Side chain chemistry imparts physicochemical properties. R= O O O N R H 3C O N N Prazosin Terazosin O N H 3C O NH2 Doxazosin O Prazocin: is an α1-blocker that acts as an inverse agonist. Structural Features: 4-amino-6,7-dimethoxyquinazolines, Piperazine nucleus, Furan carboxylic acid moiety. Terazocin: reduction of the furan ring to tetrahydofuran increases the duration of action [once daily]. Synthesis: Reaction of piperazine with 2-furoyl chloride followed by catalytic hydrogenation of the furan ring leads to compound 2. Heating of compound 2 and 2-chloro-6,7-dimethoxy- quinazolin-4-amine (1) undergoes direct alkylation to terazosin  β-adrenergic antagonists Aryloxypropanolamine derivatives. Bulky substituent on the nitrogen atom. 1) Propranolol: OHH Nonselective β-blocker. O N Used in several cardiovascular illnesses (2RS)-1-[(1-methylethyl)amino]-3-(naphthalen-1-yloxy) propan-2-ol hydrochloride Synthesis OH Cl O O + O NH2 2) Timolol Maleate Used mainly for treatment Of glaucoma. Polar heterocyclic groups minimize CNS effects. Selective β1-antagonists: 3) Atenolol: Selective β1-antagonist?. used as antiarrhythmic for bronchial asthma patient. The presence of polar substituent (acetamide) on the aryl moiety enhance the selectivity for β1-receptors. 4) Carvedilol (±)-[3-(9H-carbazol-4-yloxy)-2- hydroxypropyl][2-(2-methoxy phenoxy)ethyl]amine Non-specifically (an antagonist for β3 and for β1 or β2 adrenoceptors). Approved for medical use in the United States in 1995. It is on the World Health Organization's List of Essential Medicines. In 2022, it was the 34th most prescribed medication in the United States. Indicated in the management of congestive heart failure, commonly as an adjunct to angiotensin-converting- enzyme inhibitor (ACE inhibitors) and diuretics.  Polar aromatic rings (thiadiazole) or substituents (hydroxyl, acetamido, morpholino) decrease log P, minimizing central adverse effects. Drugs affecting NEP/EP biosynthesis Inhibitors of any of the three enzymes involved in the conversion of L-tyrosine to NEP could be used as drugs to modulate adrenergic transmission. Biosynthesis NH2 HO NH2 of COOH Rate limiting COOH Tyrosine Epinephrine HO hydroxylase HO Tyrosine Dopa decarboxylase OH HO NH2 Dopamine HO NH2 B-hydroxylase HO HO Dopamine NEP N-methyltransferase OH HO NHCH3 HO  levodopa (L-3,4-dihydroxyphenylalanine) L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot. L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. Carbidopa A powerful inhibitor of aromatic L-amino acid decarboxylase of exogenous L-dopa reducing its peripheral side effects & allow larger amount of Levodopa to cross the BBB. It acts as inhibitor of the metabolism Steroidal Hormones & therapeutically related compounds  Hormones Hormones are the chemicals (chemical messengers) that are produced and released by glands of the endocrine system, transferred through blood to the target organ to bind to a receptor and exert the desired biological effect. Classification: Chemical structure  Steroidal hormones: Estrogens & Progestins, Androgens, Glucocorticoids & Mineralocorticoids. Peptide hormones: Insulin.  Single amino acid derived hormones: T3 and T4  Fatty acids derived hormones: Prostaglandins.  Steroid Hormones Steroidal nucleus: C D Gonane (17 C) A B Cyclopentanoperhydro phenanthrine 21 Numbering sequence: 20 12 18 11 17 19 C 13 D 1 16 9 H 14 2 10 H 8 15 H A B 3 5 7 4 H Stereochemistry 21 22 20 24 18 12 17 23 25 26 11 19 C 13 D 16 1 9 H 14 27 2 10 H 8 H 15 A B 3 5 7 4 H 6 5-alpha Cholestane  H at 5 is  “natural” Rings A/B trans, B/C trans, C/D trans.  B/C and C/D fusions are all Trans, while A/B fused ring may be Cis or Trans [trans is the natural form]. The major steroidal nuclei: 18 12 18 12 17 17 11 11 C 13 19 C 13 D D 16 16 1 9 1 9 2 10 2 14 14 15 10 8 15 8 A B A B 3 3 7 5 7 5 6 4 6 4 Estrane (C18) Androstane (C19) Estrogen Androgen 20 21 21 22 18 20 12 24 17 18 11 12 23 25 26 19 C 13 D 11 17 16 1 9 19 C 13 D 16 2 1 9 14 14 15 27 10 8 2 A B 10 8 15 3 A B 5 7 3 5 7 4 6 4 6 Pregnane (C21) Cholestane (C27) Progesterone The parent of steroids Glucocorticoids & Mineralocorticoids.  Steroidal Hormones Female sex hormones Estrogen & progesterone Sex Hormones Male sex hormones Steroidal Androgen Hormones Adrenocortical Hormones Glucocorticoids Mineralocorticoids  Sex Hormones 1. Female Sex Hormones: 1.1 The Estrogens Hormonal Regulation:  Types of Estrogens Natural Semisynthetic Synthetic Estrogen Estrogens Non-Steroidal Estrogens 1. Natural Estrogens Estradiol The most potent (100%) 3,17β-Dihydroxy-Estra-1,3,5(10)-triene. Estrone (30%) 3-Hydroxy-Estra-1,3,5(10)-triene-17-one. Estriol (10%) 3,16α,17 β-Trihydroxy-estra-1,3,5(10)-triene. Structural Features:  Estrane derivatives (18 C-atoms).  Ring A Benzenoid (Unique feature).  Absence of C-19 ;Absence of side chain at C-17. Phenolic OH (ring A); C=O or OH at C-17. Physiological functions:  Development of female primary sex characters: Regulates menstrual cycle, development of uterus,vagina.  Development of female secondary sex characters: Softening of the skin and the voice  Increase HDL, slight reduction LDL so prevent atherosclerosis  Increase deposition calcium on bone. Therapeutic Uses  Primary hypogonadism: Replacement therapy [HRT]  Postmenopausal hormonal therapy  Other uses: birth control.  In prostate carcinoma: as estrogen is anti-androgen.  Metabolism: OH O Estradiol Dehydogenase 1st Pass Effect HO HO Estrone Estradiol 16α-Hydroxylase 16α-Hydroxylase OH O OH OH Dehydogenase HO HO Estriol 16a-Hydroxy-estrone Therapeutic limitations:  Cannot taken orally due to its 1st pass effect converting into Estrone.  Rapid metabolism. (Short duration).  Types of Estrogens Natural Semisynthetic Synthetic Estrogen Estrogens Non-Steroidal Estrogens I. Orally Active Estrogens II. Injectable Estrogens I. Orally Active Estrogens: Ethinyl Estradiol “EE” Angular methyl gp protects from β face Sandwich protection 17α-C≡CH gp protects from α face 17α-Ethinylestra-1,3,5(10)-3,17β-diol Oral activity: [15-20 x > Estradiol] Oral contraceptive  II. Injectable Depot Estrogens: For longer duration CH3 O CH3 O H O H O H H HO HO Estradiol-17β Valerate Estradiol-17β Cypionate CH3 OH CH3 O H O H O H O H O O Estradiol-3 benzoate Estradiol-3, 17β dipropionate  Esterification of the phenolic 3-OH and/or the alcoholic 17β –OH gps.  After IM parenteral administration, slow ester hydrolysis (Esterase Enzyme) releasing the free estradiol over prolonged time “3 months or more”.  Types of Estrogens Natural Semisynthetic Synthetic Estrogen Estrogens Non-Steroidal Estrogens  3. Synthetic Non-Steroidal Estrogens Steroidal nucleus is not essential for activity, many stilbene derivatives especially those with trans configuration have estrogenic activity (mimic the estradiol binding). Trans-diethyl stilbesterol (Trans-DES)  Orally Active.  Prostate cancer: selectivity and side effect ??? Alkene linkage 3.88 Ao (Essential) 3.88 Ao OH CH3 OH H H HO OH HO HO Cis-DES 7 Ao 12.1 Ao Inactive 10.9 Ao  E)-3.4-Bis(4-hydroxyphenyl)-hex-3-ene  Trans α, α’- diethyl-4, 4’- stilbene-diol 3. Synthetic Non-Steroidal Estrogens To be continued…….. Fosfosterol DES diphosphate ester O O P ONa ONa NaO O P NaO O  Fosfesterol is a prodrug used for ttt of prostate cancer, activated in cancer cell by phosphatase enzyme.  Fosfesterol has great water solubility (Why?) and is available for IV use.  Feminizing effect decreased (Why?).  SAR Steroidal structure Not Essential 17β-OH & 3-OH constant distance Essential Unsaturation of ring B Decreased activity OH C D Alkylation of aromatic A Decreased activity A B 17α- OH and 3-OH esterified HO For enhanced activity & Longer duration Estradiol Aromatic ring A with C-3- OH Essential  Estrogen Antagonist From Estrogen to Anti-Estrogens Estrogen Anti-Estrogens  Anti-Estrogen Receptor Aromatase antagonists inhibitors Full Antagonist SERMs Anti-estrogens:  Used for treatment of: Infertility. Estrogen-dependent breast cancer.  Estrogen Receptor antagonists are full antagonists and SERM.  Others anti-estrogens include aromatase inhibitors.  SERMs (Selective estrogen receptor modulators) Drugs with tissue selective actions. Each has distinct conformational changes. Bind strongly to the receptors & competes with estradiol for estrogen receptors.  Aromatase inhibitors: Block conversion of androgens to estrogens.  1. Estrogen Receptor Full Antagonist Fulvestrant  It is a pure antagonist.  It is charechterized by substitution at 7-α with long alkyl hydrophobic side chain.  Its oral bioavailability is poor, so used as IM "once monthly” to treat estrogen-dependent breast cancer in postmenopausal women. 2. Selective Estrogen Receptor Modulators (SERM) How SERMs acts?  These agents exhibit tissue specific estrogen agonist or antagonist activity.  Triphenylethylenes SERMs Benzothiophenes Triphenylethylenes Tamoxifen (Nolvadex) Amino ethyl side chain Essential O CH3 N CH3 Z isomer only used  Antagonist of the ER in breast tissue, Partial agonist at endometrium, bone and liver.  Used orally for treatment of ER-breast cancer in pre- and post- menopausal women. Metabolism: N-demethylation (major/ inactive) (N-demethyltamoxifen) P-hydroxylation (minor/ more active) 4-hydroxytamoxifen.  Clomiphen (Clomid) NH+ O Cl Cl NH+ O Zuclomiphen Enclomiphen  Mixture of Z & E isomers (synergistic effect).  Z ( Zuclomiphen) → Weak Agonist on bone, lipid, breast”,,, E ( Enclomiphen) → Antagonist on uterus.  They are used orally as a mixture isomers to induce ovulation for treatment of infertility. N.B: at ↑ dose of clomiphene → ↑↑ FSH → ↑ No. of mature ova → multibirth  Benzothiophenes Raloxifene (Evista)  Antagonist of the ER in breast tissue and endometrium, Partial agonist at bone and lipid metabolism.  Used orally for treatment and prevention of post-menopausal osteoporosis.  Steroidal 3. Aromatase Inhibitors Non Steroidal  These agents inhibits aromatase enzyme which catalyzes the conversion of testosterone to estradiol and androstenedione to estrone. OH OH Aromatase O HO O O Aromatase O HO 1) Steroidal aromatase inhibitors (Irreversible&Non-selective Examples: Exemestane, Formestane and Testolactone (Teslac). Exemestane (Aromasin) O CH3 most potent CH3 H H H O CH2  It has modifications in rings A and B.  It is a drug used to treat breast cancer structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme.  It might be used for treatment of gynecomastia.  2) Non-steroidal aromatase inhibitors (Reversible):  Letrozole, Fadrozole, and Vorozole inhibit the aromatase enzyme by binding of the N-4 nitrogen of the triazole ring with the heme iron atom of the CYP19 A1 enzyme complex Letrozole (Femara) CN NC N N N Orally used for: Treatment of estrogen-dependent breast cancer in post menopausal women.  Pharmaceutical Chemistry-II PHC 422 By Dr. Esraa Zakaria Lecturer of Medicinal Chemistry Contact E-mail: [email protected] O6U  Sex Hormones 1. Female Sex Hormones: 1.2 The Progestins  Progestins & Anti-Progestins Natural Semisynthetic Anti- Progestins Progestins Progestins  20 21 18 12 1. Natural Progestins 1 19 11 9 C 13 D 17 16 2 14 10 8 15 A B 3 5 7 4 6 Pregnane (C21) Ring A is NOT aromatic Progesterone (21C) Pregn-4-en-3,20-dione  It is a female sex hormone secreted mainly by corpus luteum (ruptured follicle in ovary) and in pregnancy by placenta. Therapeutic uses and pharmacological actions: With estrogens,,,, Progesterone controls:  Normal menstrual bleeding.  Preparation of uterine endometrium to receive the fertilized ovum.  Suppression of the ovulation during pregnancy, maintenance of pregnancy via depression of uterine contractility. Progesterone used for:  Hormonal contraception (either alone or with an estrogen)  Hormonal replacement therapy.  Anticancer as prostate carcinoma.  20 21 18 12 Metabolism: 1 19 11 9 C 13 D 17 16 2 14 10 8 15 A B 3 5 7 4 6 Rings A & B Progesterone Cis configuration O OH O OH O HO O H OH 5β-reductase 6 α-Hydroxy Progesterone 17α-Hydroxy Progesterone 5β-Pregnan-3,20-diol Limitations of progesterone:  Not taken Orally Development of orally active (Inactive hydroxylated metabolites). derivatives with no androgenic  Short Duration activity has been a priority.  Masculinization & Hirsutism in women.  2. Semisynthetic Progestins i. Pregnane derivatives “17α-hydroxy derivatives”  17α-Hydroxy Esterification : *Lipophilicity increase ( longer duration) *Metabolically stable (α- face protection of the carbonyl from keto reductase & β β-face protected by the angular methyl). *Used orally and parenteral. O O CH3 (CH2)4CH3 O O O O O O 17α-Hydroxyprogesterone 17α-Hydroxyprogesterone hexanoate "caproate“ acetate. “Cidolut depot injection”  17α-Hydroxy Esterification + C-6 substitution with CH3 or Cl *Lipophilicity increase (longer duration) why ??? *Metabolically stable why???  α- face protection of the C=O from keto reductase which β-face protected by the angular methyl.  Prevention of 6-hydroxylation “Obstructive Effect” & prevent reduction of 4,5 db. O O O O O O O O O O O O Cl Medroxyprogesterone Megesterol acetate Chlormadinone acetate acetate db between 6,7 positions Oral (Provera) Increased activity Parenteral (Depo provera)  ii. Androstane derivatives CH HO C O Ethisterone 17α-Ethynyl-17β-hydroxyandrost-4-en-3-one.  It was synthesized to find an orally active androgen but later it was proved to be an effective oral progestin. It is15 times more active than progesterone.  Orally used in treatment of menstrual dysfunctions, but androgenic side effect as masculinization occurred.  iii. Nor-androstane derivatives Several Modifications have enhanced the progesterone activity + Removal of keto Removal of 19 CH3 + Adding CH3 at C18 function at C3 CH CH CH AcO HO HO C C C O O Norethisterone acetate Norgestrel (racemic) Lynestrenol 17α-ethinyl-19-nortestosterone Levonorgestrel (-) *No androgenic effect. *No similarity with *About 100 x potent as *Progestational testosterone. progesterone. Activity increase *Contraceptives in *Less androgenic effect. combination with estrogen *Acetate gp (Prodrug). 3. Progesterone antagonists: Anti-progestin is a substance that competes with progesterone for its receptor and, ultimately, prevents progesterone from binding to and activating its receptor. Anti-progestin used for:  Medical abortion in the first two months of pregnancy.  Induction of Labor in the third trimester.  Postcoital Contraception.  Breast Cancer.  OH N N C CH3 C CH3 HO C C O O Mifepristone Onapristone Prevent PR-DNA Prevent transcription after PR-DNA association. association.  Sex Hormones 2. Male Sex Hormone: The Androgens  12 18 17 Natural Androgens OH 1 19 11 9 C 13 D 16 2 14 10 8 15 A B 3 5 7 4 6 Androstane (C19) O Testosterone (The major natural androgen)  Naturally occurring androgen secreted by testes under the control of LH. It is also secreted from the adrenal cortex. Two functions:  Androgenic: Normal reproduction, sexual performance ability, development and maintenance of male sex organs and secondary male sex characters (hair ,voice …………).  Anabolic: Increase protein synthesis, cause nitrogen retention & decrease protein catabolism. Therapeutic Uses:  Restore or maintain secondary sexual characteristics.  For failure of testes to descend [Cryptorchidism].  For the treatment of faulty spermatogenesis.  In both sexes, androgens are used as anabolic agents.  They are used in treatment of osteoporosis because androgens retain calcium.  Inactive Metabolites Metabolism: O OH O HO Estradiol Androstendione (Inactive) OH 17 Beta Hydroxy Aromatase Dehydrogenase O 5-Alfa-Reductase 5-Beta-Reductase Testosterone OH OH H H H H O O H H 5-Alfa Dihydrotestosterone 5-Beta DHT (Active,,,,More Potent) (Inactive) Side Effects:  Masculinization in women, leads to growth of hair on the face and change of voice (virilization,Hirsutism)  Oedema due to retention of water and Na+, K+. Limitations:  Cannot taken Orally ( 1st pass effect)  Short Duration  Anabolic/Androgenic Effect We need: (Testosterone was the 1st steroid used for  Oral Androgens its anabolic activity but due to its  Longer Duration Androgens androgenic activity , it is limited to be used as anabolic)  Trials to separate androgenic & anabolic actions.  1. Anabolic/ Androgenic Steroids I. Orally Active Androgens: OH OH HO CH3 CH3 F O O 17α –Methyl testosterone Fluoxymestrone 17β OH is protected α– 17β OH is protected α– Methyl at C17 Methyl at C17 (Metabolically Stable: C9α–F increase Anabolic Orally Active with longer activity by 20 times & duration) androgenic activity by 10 Increase length of 17alkyl times. chain →decrease activity If 17α-ethinyl,,,, Ethisterone: (Progesterone activity)  II. Injectable Androgens:  Esterification of 17β-OH (like propionate, enanthate “heptanoate”, cypionate) → more active androgenic compounds  Prodrugs administered parenteral with prolonged duration of action “slow release of the active form”. Testosterone 17β-propionate O R= CH2CH3 OR Testosterone 17β-Enanthate or (Heptanoate) O R= (CH2)5CH3 O Testosterone 17β-cypionate O R= Androgenic Activity 17α-ethinyl Progesterone activity 5α-DHT  2. Anabolic Steroids I. 19-nor Androgens  19-Nor testosterones (Estrane nucleus) show anabolic activity & low androgenic activity. OR H OH OH C2H5 C2H5 O O R = CH3(CH2)8CO Norethandrolone Ethylestrenol Nandrolone Decanoate (Deca-durabolin R)  Less androgenic activity.  More potent than  Orally Norethandrolone  Anabolic/Androgenic  CO is essenial for (4/1) the androgenic not  IM the anabolic activity.  Oral  II. Heterocyclic Derivatives  Additional heterocycle (pyrazole) at 2-3 position or isosteric replacement of 2-CH2 with O lead to increase the anabolic activity.  Doesn’t cause gynecomastia as it does not aromatize OH OH CH3 CH3 O HN N O H H Oxandrolone Stanazolol (Stanozol R) 2-Oxa-Steroid.  III. Hydroxylated & Dehydro analogs of 17α-methyl testosterone  Derivatives have at least three times the anabolic and half the androgenic activity of the parent compounds.  Alkylation renders the compounds metabolically stable (Orally Active). OH CH3 OH CH3 O O OH Oxymesterone Methandrostenolone  IV. Alkylated & Halogenated 19β testosterone acetate 11 12 18 17 19 C 13 D 16 1 9 2 14 10 8 15 A B 3 5 7 4 6 OCOCH3 OCOCH3 O O H Cl Methenolone Acetate Chloro testosterone Acetate Alkylation increases the Halogen sub decrease anabolic activity. activity except at position 4 & 9. Anabolic activity  Androgen Antagonists Steroidal I. Receptor Antagonists Non- Steroidal II. 5α -Reductase Inhibitors Medicinal Uses: In females: Treatment of acne, virilization (hirsutism). In males: Treatment of prostate cancer, benign prostatic hyperplasia & early puberty.  Androgen Antagonists I. Receptor Antagonists  Compete with DHT for the human prostate androgen receptor. Steroidal anti-androgens Non- Steroidal anti-androgens O O O2N Cyclopropane O O F3C N H O Cl Cyproterone acetate Flutamide  Semisynthetic  Synthetic, pure antiandrogen  High affinity to androgenic (selective) used for ttt of receptor. prostate cancer.  Progesterone derivative.  II. 5α -Reductase Inhibitors 5α DHT is important for maintaining prostate function in men. Blocking this enzyme is an important approach for controlling androgen action. O NH O N H Finasteride (Proscar) It is an aza steroid (aza-androst-1-ene) used to irreversibly inhibit 5α reductase enzyme,,,leading to decrease androgen biosynthesis and activation in target tissue. CNS Depressants II) Sedatives & Hypnotics  II) Sedatives & Hypnotics Sedatives are drugs which exert a quieting effect accompanied by relaxation and rest but do not necessarily induce sleep. Used as anxiolytic. Hypnotics are drugs which induce sleep and its action from slight sedation to sleep according to the drug used, dose & its route of administration. Uses of Sedatives: 1. Great emotional stress. 2. Chronic tension state created by a disease. 3. Hypertension. 5. Control convulsion. 6. Adjunct to anesthesia. Uses of Hypnotics: To overcome insomnia. Dose dependency Classification They belong to a wide variety of chemical compounds Benzodiazepines Barbiturates. Chloral Piperidinedione. Cyclopyrrolones and imidazopyridine. 1. Benzodiazepines “BZDs”: M.O.A; discussed previously Drugs: Diazepam Temazepam Chlorazepate Midazolam discussed previously Nitrazepam Flunitrazepam Clonazepam Lormetazepam  2. Barbiturates: 5,5-diethylbarbituric acid was the first sedative hypnotic used in 1903. Many members were then added until the appearance of benzodiazepines which have much greater margin of safety. They are 5,5-disubstituted barbituric acid derivatives. For good hypnotic activity; Barbiturates must be weak acids, and must have Good Lipid /water partition coefficient.  M.O.A  They bind to specific barbiturate site which present beside GABA receptors on Cl channel and this lead to enhance GABA effect and opening of Cl- channel → Cl influx → ݄‫ ݊݋݅ݐܽݖ݅ݎ݈ܽ݋݌ݎ݁݌ݕ‬lead to inhibition of neural activity.  Barbituric acid Pka = 4.12, 5-mono subsituted derivative Pka = 4.75.  At physiologic PH they are ionized i.e polar so cannot penetrate BBB.  5,5 Disubstituted BA has Pka = 7.6 without substitution on the nitrogen. While those with a methyl substitution pka = 8.4. So, at physiologic pH they will be in non-ionic lipid soluble form  5,5-Disubstituted or 1,5,5-trisubstitutedare only active. Thus, for good barbiturate activity, we need: 1. Weak acid (N1 and N3-disubstitution results in non-acidic inactive compounds). 2. Partition coefficient (to certain limit; if too hydrophobic the drug cannot dissolve in body fluids) SAR C-5: C5-H atoms must be disubstituted (sum of both substituents should be 6-10 Carbons). Branching, unsaturation, replacement of alkyl gp with alicyclic or aromatic gps → all lipid sol → potency. Introduction of halogen atom into 5-alkyl subs → potency. Introduction of polar gp (OH, NH2, RNH, CO, COOH & SO3H) to 5-alkyl gp → lipid sol → destroys the potency. N atoms: Methylation of N1 or N3 → lipid solubility → quick onset. Substitution of both N atoms → non-acidic → inactive. O atoms: Replacement of C=O by C=S → lipid solubility → rapid onset & short duration (So, thiobarbiturates are used as IV anesthetics). Introduction of more S atoms (2, 4-dithio) → destroy activity ( hydrophilic characters; too hydrophobic, no dissolution in body fluids). Classification: The duration of action ranging from long to ultra short acting depends on type of substituents. d) Ultra short acting: Methohexital Thiopental. Na General anesthetic Metabolism: Barbiturates lose their activities through hepatic metabolism. Start losing lipophilicity → CNS concentration → activity. N-demethylation: is slowly produced and slowly eliminated → metabolite accumulation with parent barbiturate Barbiturate abuse, and Disadvantages: Prolonged use leads to habituation, tolerance to increase dose. Barbiturates are notorious for their enzyme induction. It should be careful when co-administered with drugs which are mainly eliminated through hepatic metabolism. They induce their own metabolism → leading to rapid metabolism of the barbiturate → Tolerance Respiratory depression 3. Chloral: Trichloro acetaldehyde monohydrate CCl3CH(OH)2 Mode of action: It acts on GABA receptors → [bind to other site than Barbiturates & BZB, all enhance GABA inhibitory effect centrally. Advantage: not cause respiratory center depression. Disadvantage: Unpleasant odour & taste. GIT irritant → nausea & vomiting. 4) Piperidine Diones: 5) Melatonin-1 receptor (MT1 ) agonists  Melatonin is and endogenous substances, responsible for control of the circadian rhythm of life.  Chemically it is N-acetyl-5-methoxytryptamine.  known as the hormone of darkness. As a drug: it is a poor hypnotic, poor adsorption, poor oral bioavailability, rapid metabolism, and might result in drug because.  There are several receptors (e.g. M1 & M2). O O NH CH3 NH CH2 CH3 H HN O OCH3 Melatonin Ramelteon  O 1) Ramelteon: NH CH2 CH3 Synthetically modified Melatonin by H replacing the NH of the indole ring by CH2 to give indane ring and incorporating 5-OCH3 group in the O indole into a more rigid furan ring “essential for binding”.  Selective MT1 agonist (8 times more than MT2 ). More effective in initiating sleep than melatonin.  It is used for treatment of insomnia  No addiction liability. O O NH CH3 NH CH2 CH3 H HN O OCH3 Melatonin Ramelteon  CNS Depressants I) Anxiolytics or Antianxiety  I) Anxiolytics or Antianxiety It is physical and emotional distress which interferes with normal life, ” a sense of apprehensive expectation that will be pathological when it is either inappropriate or in an excess” Types of anxiety 1- Generalized anxiety disorder (GAD). 2- Panic attack. 3- Phobias. 4- Obsessive compulsive disorder (OCD). 5- Post-traumatic stress disorder. Causes 1- Drugs (alcohol abuse, chronic exposure to organic solvents in the work can be associated with anxiety disorder. 2- Stress. 3- Genetic 4- Evolutionary mismatch Mechanisms 1- Biological (GABA, serotonin). Treatment 1- Life style change (reduce caffeine intake, stopping smoking) 2- Psychotherapy (teaches different ways of thinking, behaving or reacting) 3- Medications (benzodiazepines, SSRI, beta- blockers (taken in low doses)). Antianxiety agents involve:  Benzodiazepines  Azolobenzodiazepines “Azolams”  Non benzodiazepine (Z-drugs)  GABAA-partial allosteric modulators  Atypical azaspirodecanediones  Melatonin-1 receptor (MT1 ) agonists 1. Benzodiazepines “BZDs”: M.O.A: The biological target: GABAA (GABA agonists). BZDs combine to a receptor that is present next to GABA receptor “allosteric” (BZR1 & BZR2) → increasing the action of GABA →↑opening chloride channels. Which ↑ in Chloride ions entering nerve cell → hyperpolarization of the neuron. → inhibitory effect and antianxiety effect. Thus BZDs enhance the inhibitory effect of GABA. So, they are positive modulators of GABA BZ are less Lipophilic than barbiturate, have active metabolites, and more effective as antianxiety agents.  Mechanism of Action 11/4/2024 6 SAR R: alkyl is optimal 1,2 fused imidazole, “small” triazole enhance activity H-bond accepting 6,8,9 not substituted group: C=O important R 2 O 3-OH active, 9 N Aromatic > 8 1 short duration, heteroaromatic A B 3 more polar X 7 N 6 5 4 Alkyl decreases EWG activity C 5-phenyl 4,5 DB important increases activity EWG increases Activity (position: 2 or 2,6)”ortho or di ortho” P-substit. decreases activity 1. Benzodiazepines “BZDs”: 1.4 Benzodiazepines 1.5 Benzodiazepines 3H 1.4 Benzodiazepines 2H 1.4 Benzodiazepines Chlordiazepoxide a) Lactams: - Diazepam Nordazepam Prazepam Halazepam Quazepam Flurazepam b) Hydroxylactams: Oxazepam Lorazepam BZDs another Classification: 1,4-Benzodiazepin-2- 1,4-Benzodiazepin- 1,2-Annelated-1,4- ones. 4-oxide Benzodiazepine 1,4-Benzodiazepin-2-ones Examples The prototype metabolized to many active metabolites,  1,4-Benzodiazepin-4-oxide. Chlordiazepoxide HCl (Librium) The first effective BZ for clinical use with wide range of safety than barbiturates. Rapidly absorbed and bio transformed to several active metabolites. Metabolism C-1,2-Annelated 1,4 benzodiazepine. “Azolams” v v Azolams ‘Azolobenzodiazepines” 2. Atypical Anxiolytic “azaspirodecanediones”: Azaspirodecanedione O 5 6 Buspirone N 2 3 N1 4 7 N N 8 10 9 N HCl O  It is an azaspirodecanedione derivatives  It alleviates anxiety without sedation.  It does not possess anticonvulsant or muscle relaxant. It acts as partial agonist of serotonin at 5HT1A receptors.  It has also antidopaminergic activity. 15  Medicinal Chemistry-II Fall 2024-2025 1  Antipsychotics (Neuroleptics) Drugs that are used for treatment of mental illness. psychosis Mental illness neurosis mood disorder  The mostly accepted etiology of mental illnesses is due to increased dopaminergic neurotransmission. Antipsychotic drugs are used for treatment of psychosis by reducing dopaminergic activity in brain. Chemical classes:  Phenothiazines (Typical)  Phenothiazine analogs: a)Thioxanthenes, b) Dibenz(aza/oxa/thia)azepines (Atypical)  Fluorobutyrophenones.  Miscellaneous agents: (Benzamides; Benzisoxazoles; 5 Lithium carbonate). 6 S 4 7 3 1) Phenothiazines 8 2 10 Structural Features 9 N 1 R1 Typical antipsychotic drugs (CH2)nR2  First Generation  They are classified according to the type of substitution on the terminal nitrogen atom into three main classes:  Promazines: Propyldimethyl amino  Ridazines: Alkylpiperidinyl-  Perazines: Propylpiperazinyl-  N N N N R N CH3 N N N CH3 N R R Propyldimethylamino- -Alkylpiperidyl Propylpiperazinyl- (Promazines) (Ridazines) (Perazines) Perazines are the most active and promising derivatives. Most of phenothiazines are used as salts (e.g HCl salt) 4  Perazine (propyl piperazine derivatives) S 1) Fluphenazine The most active N CF3  Low sedative & autonomic effects. N N CH2CH2OH 2) Fluphenazine decanoate S Long acting with fewer side effects. Depend on N CF3 esterification of a free OH group with long chain fatty N acid. One (IM) injection /2-3 N(CH2)2OCO-(CH2)8-CH3 weeks Mode of action Typical antipsychotic drugs act by blocking dopamine (D2) receptor (presynaptic and postsynaptic). Structures of chloropromazine and dopamine Chloropromazine 6 Structure Activity Relatioship (SAR) X  It is postulated that phenothiazines interact Site A with the receptor at three H R N S distinct sites, A; B; and C. N N The highest degree of H3C Site B Site C specificity is required for site B followed by C then A Site A: The side chain basic nitrogen R 1) Tertiary nitrogen is essential. N R 2) Dimethylamino has maxim. activity, diethylamino is less active, cyclic amine is also active e.g piperidine or piperazine. 3) Quaternization of the nitrogen atom reduces lipid solubility resulting in decreased penetration to the brain and loss of central activity. 7 4) In case of N-hydroxyethylpiperazine derivatives, the duration of action could be increased by esterification of the N-alkylhydroxy with long chain fatty acids (Fluphenazine decanoate). Phenothiazine N Site B: The side chain 1 3 R 1) Three C-atoms chain is the optimal length 2 N for activity. R 2) Two C-atoms chain results in moderate CNS activity, predominant antihistaminic activity. 3) Part of additional ring decreases the activity due to free rotation of the side chain is necessary. 4) Non-substituted β carbon gives best CNS activity, branching decreases neuroleptic activity by affecting the receptor binding, (introduction of methyl substituent enhances the antihistaminic activity). 8  X Site C: The phenothiazine nucleus 1) The molecule is folded along the N-S axis with the two flat benzene rings at right angles. N S The X substituent is far from the receptor surface to exert any steric effect. Site C 2) Only position 2 is susceptible for substitution. 3) Any substitution at positions 1, or 4 or simultaneous, substitution on both rings give inactive compounds, 3 is active but less than 2. Any substitution at 1- position interferes with ability of the side chain to bring protonated amino into proximity with the 2-substituent. Any substitution at 4-position interferes with receptor binding (Steric factor) i.e decrease activity. 9  X 4) The nature of X substituent:  X = H inactive , electron withdrawing (Cl, CF3, SO2N(CH3)2), will increase the activity S N (CF3 is the optimal).  Electronegative atom is responsible for Site C imparting asymmetry to molecule & attraction of the amine side chain (protonated at physiological PH) toward ring bearing this atom.  Thioalkyl and acyl substituents give active compounds with least side effects.  Ionizable groups e.g. OH reduce the activity? 5) Position-5: S-atom is assigned for receptor binding function, S-atom is analogous to p-hydroxy group of dopamine. 10  Tertiary nitrogen is essential. X subst.is far from the receptor surface.  Secondary decrease activity.  X = H inactive  Quaternary loss of activity.  X = eletronegative atom e.g halogen  Cyclic amine active.  X = SCH3 or COCH3 active, less SE  Increase duration of action in  X = OH inactive WHY? piperazine derivative by esterification. S-atom is assigned for receptor binding X function, S-atom is analogous to hydroxy group of dopamine. Site A R  The phenothiazine is folded H R S N N along N-S axis with 2 flat benzene at right angles. Site C  Position 2 is susceptible for R Site B substitution.  Subst. at 1 and/or 4 inactive  3-Subst. is moderate.  3 C-atoms chain is the optimal length for activity.  2 C-atoms chain moderate antipyschotic activity (antihistaminic activity).  Part of additional ring decreases the activity (free rotation is essential).  Branching decreases activity (β CH3 enhances the antihistaminic activity).  Metabolic pathways Oxidation, Sulfoxide) Hydroxylation S N X Dealkylation Mono- or Didealkylation CH2CH2CH2N Monomethyl metabolite is biologically active (Less)  2) Phenothiazine analogs a) Thioxanthenes b) Dibenzo(aza/oxa/thia)azepines) a) Thioxanthene derivatives A group of neuroleptics derived by isosteric replacement of the ring N-atom of phenothiazine with C-atom doubly bonded to propyl side chain, Z and E isomers are produced. The isomer (Z) is more active than the (E) form. They share many clinical properties with phenothiazines.  S Flupentixol decanoate CF3  Long acting thioxanthene N NCH2CH2-OCO(CH2)8CH3 (1-2 weeks).  Similar to Fluphenazine decanoate.  Z isomer is active b) Dibenzazepine analogs X = O dibenzoxazapines X = S dibenzothiazapines X = N dibenzodiazapines Olanzapine H3C S H N Thienobenzodiazepine derivative.  Effective antipsychotic agent and used for treatment of schizophrenia. N N  It is antagonist of dopamine at D2 Olanzapine N receptor, but it has higher affinity for the H3C 5HT 14 2A receptor (Atypical).  3) Fluorobutyrophenones AR O Structural features: N 4 Y 1) Aliphatic tertiary amine is 4 essential and is incorporated F Fluorobutyrophenone into cyclic ring. 2) The attachment of the tertiary N to the fourth C-atom of butyro-phenone is essential for activity. 3) Halogenated rings for receptor binding and distribution to CNS e.g. F in p-position. 4) Keto function is essential for proper activity. 5) Variations in C-atoms chain or change of the tertiary N loss of the activity. 6) AR is an aromatic ring directly attached to 4-position or separated by atom. 7) Y group can be varied and assist activity. Haloperidol,Trifluperidol, Droperidol and Spiperone  OH 1) Haloperidol F N O  A potent antipsychotic useful in schizophrenia and in psychoses.  It is often chosen as agent to terminate mania.  Haloperidol decanoate is long acting one injected (IM) every 4-6 weeks Modified butyrophenones (Diphenylbutylpiperidines)  Modification of the side chain: replacement of the C=O with 4-flurophenyl methane moiety. F CH-CH2CH2CH2 N R F N R1 O Diphenylbutylpiperidine F Butyrophenone derivatives  F Pimozide: : High hydrophopic properties O (long duration of action) CH-CH2CH2CH2 N N NH  Used in treatment of acute schizophrenia F 4) Miscellaneous agents 1) Benzamides e.g Sulpiride & Remoxipiride 2) Benzisoxazoles e.g Risperidone 3) Lithium carbonate 1) Benzamides The benzamides evolved from observation that the antiemetic agent metoclopramide has antipsychotic activity apparently related to D2 receptor block. O C2H5 Cl N N C2H5 H O H2N 17 Metoclopramide CH3 Metoclopramide/Dopamine overlay O C2H5 Cl N N C2H5 H H2N O CH3 Metoclopramide The hypothetical dopamine-like structure in metoclopramide is through the H-bond between the amido H and the unshared electrons of methoxy group, to generate a pseudo