بسم الله الرحمن الرحيم

By Prof. Dr/ Nadia Mahfouz Pharm. Chem. Department CNS Drugs (6 hr) Steroidal Hormones (3 hr) By Prof. Dr/ Nadia Mahfouz Pharm. Chem. Department October 6 University 2018-2019 8/7/2019

Lecture…Lecture…Lecture 8/7/2019 References Lecture…Lecture…Lecture Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, J.N.Delgado and W.A.Remers eds., 13th edition, Lippincott-Raven, Philadelphia, (2012). T. L. Lemke, D.A. Williams, V. F. Roche and S. W. Zito: Foye’s Principles of Medicinal Chemistry 8th edition, Lippincott Williams & Wilkins, Philadelphia, (2013). Burger’s Medicinal Chemistry, M. E. Wolf ed 7th edition, John Wiley and Sons NY (2010). 4. Allen, Loyd V., Jr Remington: The Science and Practice of Pharmacy. 22nd Ed, (2012). 5. Pharmaceutical chemistry notes 2017/2018 8/7/2019

Objectives principles that highlight modern medicinal chemistry 1) It is planned to provide students with the fundamental principles that highlight modern medicinal chemistry aspects of the following classes of central nervous system (CNS) drugs which including CNS depressants and stimulants. 2) The students study in this lecture general anesthetics and sedative hypnotics as a class of CNS depressants. 2) It is necessary to identify and learn the students chemical structures, chemical nomenclatures, generic names of drugs of each group. 3) The students should also study the mechanism of action, identify the pharmacophoric moieties and their effects on their pharmacological activity. 4) It is necessary also to learn the students the method of synthesis and analysis of each drug. 5) The students study also the biotransformation of each drug in the class member. 8/7/2019

CNS Drugs Central Nervous System: Brain Spinal cord CNS Depressants (4hr) CNS Stimulants (2hr) Central Nervous System: Brain Spinal cord Brain is the most complex organ. It works into two opposing forces, excitation (stimulation) and inhibition (depressing) ANATOMY SUMMARY: The Central Nervous System 8/7/2019

CNS Depressants Depression of neuronal activity in CNS leading to slow down or depress the CNS function. General Anesthetics. Sedatives & Hypnotics. Psychotherapeutic Drugs. Anxiolytics & Antipsychotics Anticonvulsants. Analgesics. Central Muscle Relaxants Brain Spinal cord 8/7/2019

I) General Anesthetics 1) Inhalation Anesthesia What are General Anesthetics? CNS depressants that produce controlled and reversible loss of consciousness and sensation. These Drugs block the transmission of pain. Classification 1) Inhalation anesthetics (Volatile General Anesthetics) 2) Parenteral (Injectable) anesthetics (basal) 1) Inhalation Anesthesia 8/7/2019

Halogen What are drugs used as inhaled anesthetics? Nitrous Oxide (N2O): (dentist , 1844) (Ph Eur monograph 0416): N2O 44.01 Action and use: General anaesthetic; analgesic. Low potency , cause hypoxia and used in combination with more potent anesthetics for surgical anesthesia, popular anesthetic in dentistry and undergoes no metabolism. It causes euphoria. Gases Low boiling points Liquids Diethyl ether, Chloroform How? Halogen 8/7/2019

Fluronated Ethers (Fluranes) Halogenated Inhaled General Anesthetics Advantages: Potent and non flammables A) Halogenated Hydrocarbons: Halothane: It causes hepatic toxicity because about 20% of dose is metabolized to toxic metabolite. (Trifluoroacetic acid) B) Halogenated Ethers: Fluronated Ethers (Fluranes) Enflurane (RT depression, cardiac arrhythmias, convulsion) 2) Isoflurane 3) Desflurane 4) Methoxyflurane (causes nephrotoxicity) 5) Sevoflurane 8/7/2019

Sevoflurane Chemical Nomenclature??? 1-(Trifluoromethyl)-2,2,2-Trifluoroethyl fluoromethyl ether Higher potency and non-irritating to respiratory tract Similar to desflurane in its pharmacologiocal actions Low blood solubility, blood/gas PC is 0.6 (Induction and recovery are rapid) Incidence of nephrotoxicity or hepatic toxicity is low. 3% of the administered dose can be metabolized. 8/7/2019

Fluoride impurities in liquid anesthetics Aqueous extract made alkaline with NaOH and titrated with thorium nitrate using alizarine sulfonate as indicator till pink color is formed. Th(NO3)4 + F- ThF4 (nonionisable) Excess Th(NO3)4 Alizarine sulfonate 8/7/2019

What is the mechanism of action? 1. Meyer-Overton theory: Lipid soluble drug interacts with the cell membrane results in disrupted of the phospholipid bilayer and directly prevent normal ionic conductance and produced anesthesia. 2. Ion Channel and Protein receptor hypothesis: General Anesthetics interact with receptors in CNS that allosterically modulate the activity of ion channels (e.g. chloride, sodium, potassium , calcium channels). GABAA receptor: Inhaled Anesth. enhance chloride ion Conductance into cell Lead to hyperpolarize the cell membrane and prevent pulse. 8/7/2019

2) Injectable (Basal) Anesthetics Agents that achieve certain degree of unconsciousness before inhalation anesthesia, they include: Ultrashort acting barbiturates e.g thiopental, thymilal Cyclohexanone derivatives e.g ketamine Phenol derivatives e.g propofol Imidazole derivatives e.g etomidate 8/7/2019

1) Ketamine Hydrochloride (BP 2004) .HCl Norketamine Active metabolite Chem. Nomenclature: (±)- 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone S(+) is 2-3 times more potent than R(-) Very potent, rapidly acting anesthetic agent, it used IV or IM Short duration of anesthetic activity (1.0 – 2.5 min). One of its metabolites is Nor-ketamine (major) , which retains significant activity at the NMDA receptor and may account for some of the longer lasting effects of ketamine (1/3 potency of ketamine). Ketamine acts as noncompetitive antagonist at NMDA receptor. 8/7/2019

Etomidate 2) Imidazole derivative Imidazole carboxylic acid derivative. Marketed as more potent R(+) isomer. Water insoluble, oil soluble, rapidly penetrates into brain. Rapidly metabolized in plasma and liver via esterases. Exert anesthesia via positive modulation of GABAA receptor.

Q1: Mention the generic name and chemical nomenclature of each following drugs (1) (2) (3) (4) Q2: Draw the structure of the toxic metabolite of drug #1 Q3: Mention by equation a method for determination of fluoride impurity of any drug (#1 or 2). Q5: Mention the chemical group of drugs # 1 - 4 Q6: Fluranes including drug # ………………………………. Q7: Mention the generic name, chemical nomenclature and route of administration of the given drug 1-4) Q8: Draw the structure of an active metabolite of drug # 3 Q9: Mention the mechanism of action of drugs 1, 3 &4 8/7/2019

II) Sedatives Hypnotics 8/7/2019

Ideal Sedative hypnotic causes normal sleeping. Sedatives Hypnotics: Produce nonselective reversible depression of CNS. Cause drowsiness and facilitate the initiation and maintenance of sleep, they are dose related. Lower dose Sedative Higher dose Hypnotic Sedatives: mild CNS depressant, cause quieting effect and relaxation but not induce sleep. Hypnotics: Strong CNS depressant, produce sleep. Ideal Sedative hypnotic causes normal sleeping. 8/7/2019

Characters Certain common physicochemical and structural features. All compounds contain polar and non-polar moieties. The polar moiety (high hydrophilic characters). Their structures generally resist metabolism. The whole molecule has partition coefficient around 100 (Log P = 2). Activity 2 Log P 8/7/2019

Classifications of 8/7/2019

1)Barbiturates Structure Acyclic Ureides Cyclic ureides (Barbiturates)

I) Barbiturates 5,5-Disubstituted Barbituric acid Barbituric acid (Pka ~ 4) is water soluble, very polar, , hence inactive. Why??? Barbituric acid monolactim dilactim trilactim It should be substituted at position 5 to increase lipid solubility. 5,5-Disubst. or 1,5,5-trisubst. are only active The duration of action ranging from ultrashort to long depends on type of substituents. 8/7/2019

USP -al European -one Generic name R1 R2 R X Phenobarbital H O Long acting (> 6h) Phenobarbital C2H5 C6H5 H O Intermediate (3-6h) Amobarbital Short (< 3h)   Secobarbital Ultrashort Thiopental Methohexital CH3 S

Phenobarbital: Thiopental Sodium SAR 5-Ethyl-5-phenylbarbituric acid Uses: Sedative hypnotic & anticonvulsant Thiopental Sodium 5-Ethyl-5-(1-methylbutyl)-2-thiobarbituric acid sodium salt Uses: General anaethatic SAR X = O active X = S faster onset & ultrashort Acting e.g thiopental (surgical anesthetics) why? Higher partition coeffecient. R1 + R2 = 6- 10 C atoms. Branching & unsaturation produce higher activity and short duration. Aromatic or alicyclic increases potency & long duration. 5-Phenyl gives higher lipophilicity ( anticonvulsant activity) Polar substituents abolish activity!! 8/7/2019

Mechanism of Action 8/7/2019

Miscellaneous Alcohols NonBarbiturate sedative hypnotics Chloral hydrate CCl3CHO.H2O Relatively save sedative hypnotic, inducing sleeping within half an hour and lasting for 6 hours. It used mainly in children and elder, and patients when failed to other drugs. It is metabolized into trichloroethanol (active), trichloroethanol glucuronide and trichloroacetic acid (inactive). It exerts its action through enhancing the binding of GABA to its receptor as barbiturates and benzodiazepines. 8/7/2019

Disadvantages of Chloral Hydrate : bad taste and odour Its adducts with betaine (1:1) CCl3CH(OH)2 : (CH3)3N+-CH2COO- or with pentaerythrytol (4:1) do not have these disadvantages. 8/7/2019

Recent Sleep inducing agents 8/7/2019

Classification 1) Z-drugs Zolpidem Z-Drugs Melatonin-1 receptor (MT1 ) agonists 1) Z-drugs Highly selective for α1 subunit of BzR binding site on GABAA they include: 1) Zolpidem, Imidazopyridine derivative 2) Zaleplon, Pyrazolopyrimidine derivative 3) Zopiclone and esZopiclone, Pyrrolone derivatives Zolpidem Imidazopyridine derivative Rapid onset of action and good oral bioavailability (lipophilic and has no ionizable group at physiological pH Short acting hypnotic, (metabolizes to inactive compounds). Most common drug prescribed for insomnia. 8/7/2019

2) Melatonin-1 receptor (MT1 ) agonists Activation of MT1 receptor results in sleeping Its endogenous ligand, melatonin (N-acetyl-5-methoxytryptamine) hormone of darkness, is N-acetylated and O-methylated product of serotonin and is biosynthesized and release at night. Melatonin is a poor hypnotic drug because of its poor potency, poor adsorption, poor oral bioavailability, rapid metabolism and nonselective effects. Melatonin was modified by replacing the NH of the indole ring by CH2 to give indane ring and by incorporating 5-OCH3 group in the indole into a more rigid furan ring, this modification results in Ramelteon Ramelteon 8/7/2019

Ramelteon It is more effective in initiating sleep than melatonin. It is a MT1 selective agonist (8 times more than MT2 ). It is more effective in initiating sleep than melatonin. It is more efficacious than melatonin but less than benzodiazepines as hypnotic. It has no addiction liability. It has recently approved for treatment of insomnia. 8/7/2019

for the compounds which are inactive and the class of the active one Q1: Which of the following compounds are active as sedative hypnotic, giving reasons for the compounds which are inactive and the class of the active one (long, intermediate, short, ultrashort acting) Q2: Mention the chemical nomenclature of compound # 3 in Q1 Q3 Mention the mechanism of action of barbiturate Q4: Mention the chemical class of drug #5 Q5: Draw the structures of metabolic products of drug # 5, are these metabolites active or inactive? Q6: How you can overcome the bad taste and odour of drug # 5? (5) 8/7/2019

Q7: Mention the generic name, use and chemical group of the given drug. Q8: Is this drug short or long acting, justify your answer. Q9: mention the generic name of the given compound Q10: Can this compound used as hypnotic? Why? Q11: Carry out modifications of the given lead compound to obtain a hypnotic drug. Q12: What is the advantages of the obtained drug than the lead compound 8/7/2019