Psychotherapeutic Agents.ppt

SOPH 322 MEDICINAL CHEMISTRY I PSYCHOTHERAPEUTIC AGENTS ANAETHETICS, SEDATIVE - HYPNOTICS Mahmood Brobbey Oppong (BPharm; MPhil; PhD; MPSGH) Senior Lecturer Dept. of Pharm. Chem., UGSOP 1 Email: [email protected]; [email protected] ...

SOPH 322 MEDICINAL CHEMISTRY I PSYCHOTHERAPEUTIC AGENTS ANAETHETICS, SEDATIVE - HYPNOTICS Mahmood Brobbey Oppong (BPharm; MPhil; PhD; MPSGH) Senior Lecturer Dept. of Pharm. Chem., UGSOP 1 Email: [email protected]; [email protected]  CONTENT Introduction Classification Mechanism of action Structure Activity Relationships Synthesis Assay 2 ANESTHETIC AGENT 3  INTRODUCTION Anesthesia is defined as a loss of sensation with or without loss of consciousness. Anesthesia can be effectively achieved with a wide range of drugs with very diverse chemical structures. These compounds include not only the classic anesthetic agents, such as the general and local anesthetics, They also include many central nervous system (CNS) depressants, such as analgesics, sedative/hypnotics (barbiturates and benzodiazepines), anticonvulsants, and skeletal muscle relaxants. 4  INTRODUCTION Although various mechanisms of action are attributed to these agents, ultimately, they all produce their anesthetic actions by interfering with conduction in sensory neurons and sometimes motor neurons. Many of these agents are routinely used today in clinical practice to facilitate surgical and medical procedures. 5  GENERAL ANAESTHETIC AGENT Prior to the mid-1800s, pain-producing surgical and dental procedures typically were undertaken without the aid of effective anesthetic agents. Chemical methods available at the time included intoxication with ethanol, hashish (cannabis), or opium, Physical methods included packing a limb in ice, creating ischemic conditions with tourniquets, inducing unconsciousness by a blow to the head, or the most common technique, employing strong-armed assistants to hold down the helpless patient during the entire painful surgical procedure. First demonstration by the Hartford dentist Horace Wells of the use of nitrous oxide as a general anesthetic for surgery in 1844. 6  GENERAL ANAESTHETIC AGENT William Morton, a Boston dentist in 1846, also demonstrated the anesthetic effects of diethyl ether. Today, diethyl ether is no longer used in procedures because of its toxicity and dangerous physical properties (e.g., it is flammable and explosive!). Other general anesthetic agents that enjoyed early popularity were chloroform and cyclopropane. Chloroform vapor depresses the CNS of a patient, allowing a doctor to perform various otherwise painful surgical procedures. Chloroform was abandoned due to its cardio and CNS toxicity. 7  CHARACTERISTICS OF THE IDEAL GENERAL ANESTHETIC AGENT Rapid and pleasant induction of surgical anesthesia Rapid and pleasant withdrawal from surgical anesthesia Adequate relaxation of skeletal muscles Potent enough to permit adequate oxygen supply in mixture Wide margin of safety Nontoxic Absence of adverse effects Nonflammable/nonexplosive Chemically compatible with anesthetic devices Nonreactive Inexpensive 8 STAGES OF GENERAL ANESTHESIA 9  MECHANISM OF ACTION OF THE ANESTHETIC AGENTS Meyer-Overton Theory Hans Meyer and Charles Overton suggested that the potency of a substance as an anesthetic was directly related to its lipid solubility. This has commonly been referred to as the “unitary theory of anesthesia.” They used olive oil, octanol, and other “membrane-like” lipids to determine the lipid solubility of the agents available at that time. Compounds with high lipid solubility required lower concentrations (i.e., lower MAC) to produce anesthesia. Modern theories about the mechanisms of anesthesia suggest that a single molecular target for anesthetic actions is no 10 longer required.  MECHANISM OF ACTION OF THE ANESTHETIC AGENTS Ion Channel and Protein Receptor Hypotheses The effects of anesthetics are due to interaction on a number of protein receptors within the CNS. Interaction of the anesthetics with receptors that allosterically modulate the activity of ion channels (e.g., chloride and potassium) or with the ion channel directly (e.g., sodium). 11  CLASSIFICATION OF ANESTHETIC AGENTS General anesthetics Inhalational Intravenous Local anesthetics 12  S.A.R. OF INHALAED GENERAL ANESTHETICS Examples of inhalational anesthetic agents are nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane. There is no single pharmacophore for the inhaled anesthetics, the chemical structure is related to the activity of the drug molecule. The potency of alkanes, cycloalkanes, and aromatic hydrocarbons increases in direct proportion to the number of carbon atoms in the structure up to a cutoff point. Within the n-alkane series, the cutoff number is 10, with n- decane showing minimal anesthetic potency. In the cycloalkane series, the cutoff number in most studies 13 is eight with cyclooctane showing no anesthetic activity in the rat.  S.A.R. OF INHALAED GENERAL ANESTHETICS The reduced activity of the compounds beyond their cutoff number could be a result of problems getting to the site of action (reduced vapor pressure or high blood solubility) or inability to bind to the site of action and induce the conformational change required for anesthetic action. The cycloalkanes are more potent anesthetics than the straight chain analog with the same number of carbons. For example, the MAC of cyclopropane in rats is about one fifth of the MAC of n-propane. 14 STRUCTURES OF INHALED GENERAL ANESTHETICS 15  S.A.R. OF INHALAED GENERAL ANESTHETICS EFFECT OF HALOGENATION/ETHER HALOGENATION Halogenating the ethers decreased the flammability of the compounds, enhanced their stability and increased their potency. Higher atomic mass halogens increased potency compared to lower atomic mass halogens. For example, replacing the fluorine in desflurane (CF2HOCFHCF3) with a chlorine to form isoflurane (CF2HOCClHCF3) increased potency more than fourfold. Replacing the chlorine with bromine in the investigational agent I- 537 (CF2HOCBrHCF3) increased potency threefold further. In general, halogenated ether compounds also caused less laryngospasms than unhalogenated compounds. 16  SAR OF INHALAED GENERAL ANESTHETICS EFFECT OF HALOGENATION/ETHER HALOGENATION Unfortunately, halogenation also increased the propensity of the drugs to cause cardiac arrhythmias and/or convulsions. Halogenated methyl ethyl ethers were found to be more stable and potent than halogenated diethyl ethers. For the n-alkane series, fully saturating the alkane with fluorine abolished activity except when n =1 When n was 2 to 4 carbons the highest potency was seen when the terminal carbon contained one hydrogen (CHF2(CF2)nCHF2). 17  S.A.R. OF INHALAED GENERAL ANESTHETICS EFFECT OF SATURATION Molecular flexibility of the inhaled anesthetics is not required. The addition of double and/or triple bonds to small anesthetic molecules having 6 carbon atoms or less increases potency. 18  INTRAVENOUS GENERAL ANESTHETIC AGENTS PROPOFOL (GROUPS 5 and 7) KETAMINE ( GROUPS 4 and 3) ETOMIDATE ( GROUPS 6 and 2 ) MIDAZOLAM ( GROUPS 1 and 8 ) Presentation outline Synthesis Assay Mechanism of action Structure Activity Relationship Metabolism Storage 19  LOCAL ANESTHETICS Local anesthetic agents are drugs that, when given either topically or administered directly into a localized area, produce a state of local anesthesia by reversibly blocking nerve conductances that transmit the sensations of pain from this localized area to the brain. Unlike the anesthesia produced by general anesthetics, the anesthesia produced by local anesthetics is without loss of consciousness or impairment of vital central cardiorespiratory functions. Local anesthetics, in contrast to analgesic compounds, do not interact with the pain receptors or inhibit the release or the biosynthesis of pain mediators. 20  SARs of LOCAL ANESTHETICS The structure of most local anesthetic agents consists of three parts as shown below. (a) a lipophilic ring that may be substituted, (b) a linker of various lengths that usually contains either an ester or an amide, and (c) an amine group (hydrophilic) that is usually a tertiary amine with a pKa between 7.5 and 9.0. NB; Variation of the amine or aromatic ends changes the chemical activity of the drug. 21  SARs OF LOCAL ANESTHETICS The Aromatic Ring The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate through biological membranes. It is also thought to have direct contact with the local anesthetic binding site on the sodium channel. The aromatic ring is believed to interact with the local anesthetic binding site in a pi-pi interaction or a pi-cation interaction with the S6 domain of the α- component of the sodium channel. Substituents on the aromatic ring may increase the lipophilic nature of the aromatic ring. Para substitution of ester type local anesthetics with lipophilic substituents and electron-donating substituents increased anesthetic activity. The lipophilic substituents are thought to both increase the ability of the molecule to penetrate the nerve membrane and increase their affinity22at the receptor site.  SARs OF LOCAL ANESTHETICS The Aromatic Ring Substitution with an electron-withdrawing group decreased the anesthetic activity (the electron cloud around the carbonyl oxygen) The Linker The linker is usually an ester or an amide group along with a hydrophobic chain of various lengths. In general, when the number of carbon atoms in the linker is increased, the lipid solubility, protein binding, duration of action, and toxicity increases. Esters and amides are bioisosteres having similar sizes, shapes, and electronic structures. The similarity in their structures means that esters and amides have similar binding properties and usually differ only in their stability in vivo and in vitro. For molecules that only differ at the linker functional groups, amides are more stable than esters and thus have longer half-lives than esters. 23 CLASSIFICATION OF LOCAL ANESTHETICS Two basic classes of local anesthetics exist, the amino amides and the amino esters. Amino amides have an amide link between the intermediate chain and the aromatic end, whereas amino esters have an ester link between the intermediate chain and the aromatic end. Amino esters and amino amides differ in several respects. Amino esters are metabolized in the plasma via pseudocholinesterases, whereas amino amides are metabolized in the liver. Amino esters are unstable in solution, but amino amides are very stable in solution. Amino esters are much more likely than amino amides to cause allergic hypersensitivity reactions. 24  CLASSIFICATION OF LOCAL ANESTHETICS Commonly used amino amides include lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine, and ropivacaine and levobupivacaine. Commonly used amino esters include cocaine, procaine, tetracaine, chloroprocaine, and benzocaine. ASSIGNMENT – LOOK FOR THE STRUCTURES OF THESE AGENTS 25  SYNTHESIS OF PROCAINE (NOVOCAINE) Procaine, the 2-diethylaminoethyl ester of 4-aminobenzoic acid,, is synthesized in two ways. The first way consists of the direct reaction of the 4- aminobenzoic acid ethyl ester with 2-diethylaminoethanol in the presence of sodium ethoxide. The second way of synthesis is by reacting 4-nitrobenzoic acid with thionyl chloride, which gives the acid chloride , which is then esterified with N,N-diethylaminoethanol. Subsequent reduction of the nitro group by hydrogenation of the resulting ester into an amino group takes place in the presence of Raney nickel. 26  SYNTHESIS OF PROCAINE(NOVOCAINE) Procaine is a short-acting local anesthetic. It is used for reducing painful symptoms of various types, and it is widely used in infiltration, block, epidural, and spinal cord anesthesia, and for potentiating activity of basic drugs during general anesthesia. It may cause allergic reactions. 27  SYNTHESIS OF LIDOCAINE (XYLOCAINE) Lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives α-chloro-2,6-dimethylacetanilide and its subsequent reaction with diethylamine. 28  SYNTHESIS OF LIDOCAINE (XYLOCAINE) Lidocaine is the most widely used local anesthetic. Its excellent therapeutic activity is fast-acting and lasts sufficiently long to make it suitable for practically any clinical use. It stabilizes cell membranes, blocks sodium channels, facilitates the secretion of potassium ions out of the cell, and speeds up the repolarization process in the cell membrane. Clinical applications: It is used for terminal infiltration, block, epidural, and spinal anesthesia during operational interventions in dentistry, otolaryngology, obstetrics, and gynecology. It is also used for premature ventricular extrasystole and tachycardia, especially in the acute phase of cardiac infarction NB: Local anesthetics decrease the rate of depolarization of cardiac tissue, which is the rationale behind the use of lidocaine in treatment of ventricular arrhythmias. 29 SEDATIVE - HYPNOTICS 30  INTRODUCTION Sleep is a reversible process that is typified by sensory and motor inactivity as well as reduced cortical responses to external stimuli. This process is distinct from complete states of unconsciousness (e.g., coma), in which decreased cortical activity is unresponsive to all external stimuli. Development of sedative-hypnotic agents has primarily focused on: 1) agents that cause CNS depression via agonism of GABA receptors, and 2) agents that modulate hypothalamic histamine or melatonin circadian systems ~ regulate sleep and arousal. 31  INTRODUCTION The activation of GABA receptors on excitable neurons leads to membrane hyperpolarization, which facilitates an increase in the firing threshold potential and consequently reduces the likelihood of generating an action potential. Hence, agonism of GABA receptors leads to neuronal inhibition and CNS depression. GABA receptors are important targets for treatment of a variety of CNS disorders in which CNS depression provides a therapeutic benefit, including anxiety, anesthesia, convulsions and seizures, and sleep disorders. In this regard, drugs that increase GABA-mediated chloride influx provide anxiolytic, anesthetic, anticonvulsant, and sedative-hypnotic activity, whereas agent that block the chloride channel can lead 32 to  BARBITURATES Barbiturates are potent CNS depressants with sedative- hypnotic, anesthetic, and anticonvulsant activity. Approved barbiturates include amobarbital, butabarbital, pentobarbital, phenobarbital, and secobarbital. Barbiturates significantly decrease the time it takes to fall asleep (sleep latency), increase the total time of sleep, and also decrease occurrences of nighttime awakenings. Replaced by other sedative-hypnotic agents due to tolerance, dependence, potential for abuse, and a relatively low toxicity threshold that can lead to overdosage and poisoning. 33  BARBITURATES They exert most of their characteristic CNS effects mainly by binding to an allosteric recognition site on GABA receptors that positively modulates the effect of the GABA receptor-GABA binding. Unlike benzodiazepines, they bind at different binding sites and appear to increase the duration of the GABA-gated chloride channel openings. In addition, by binding to the barbiturate modulatory site, barbiturates can also increase chloride ion flux without GABA attaching to its receptor site on GABA. This has been termed a GABA mimetic effect. 34  SAR OF BARBITURATES Barbiturates are derivatives of barbituric acid (2,4,6- trioxohexahydropyrimidine) Barbituric acid is devoid of sedative-hypnotic, anxiolytic, and anticonvulsant activity. Readily synthesized by the condensation reaction between diethyl malonate and urea. Alternative barbituric acid can be produced from malonic acid and urea in which case water is produces as by product. 35  SAR OF BARBITURATES 36 NB: Read on the synthesis of barbital  SAR OF BARBITURATES Addition of 5,5-disubstituents to the barbituric backbone yields compounds with potent sedative-hypnotic, anxiolytic, and anticonvulsant activity. Barbiturates, the 5,5-disubstituted barbituric acids all possess a high degree of lipophilicity and, as weak acids, can be easily converted to sodium salts by treatment with sodium hydroxide. The 5,5-disubstituted barbituric acid backbone is the primary pharmacophore required for sedative-hypnotic activity. Esterification of either of the 1,3-diazine nitrogens decreases hypnotic activity. 37  SAR OF BARBITURATES Substitution of the nitrogens with aliphatic carbons retained anticonvulsant effects, N-methylated substituents produced weak hypnotic activity and this activity was lost upon increases in chain length or bulk. Specifically, modification of the 2-position oxygen of the barbiturate backbone with sulfur atom yields thiobarbiturate derivatives with increased lipophilicity, faster time of onset, and shorter duration of action compared to the oxy-derivatives. For example, thiopentobarbital and thiamylal have much faster onsets and shorter durations than their respective 38 oxy- congeners, pentobarbital and secobarbital, respectively BARBITURATES 39  BARBITURATES 40 NB: look for examples of ultra short acting barbiturates METABOLISM OF BARBITURATES 41  BENZODIAZEPINES Benzodiazepines are potent CNS depressants with sedative- hypnotic, anesthetic, and anticonvulsant activity. It is important to distinguish that benzodiazepines increase the frequency of channel opening, whereas barbiturates increase the duration of the open channel, and as such, the two classes of agents have distinct molecular effects on the GABA receptor Untoward effects include excessive residual next-day sleepiness, tolerance upon long-term use, and withdrawal upon discontinuation. Anterograde amnesia ~ recent events are not transferred to long-term memory (partial or total inability to remember past 42 events)  SAR OF BENZODIAZEPINES 43  SAR OF BENZODIAZEPINES Ring A In general, the minimum requirement for binding of 5-phenyl-1,4-benzodiazepin-2- one derivatives to the BZR includes an aromatic or heteroaromatic ring (ring A), which is believed to participate in π-π stacking with aromatic amino acid residues of the receptor. It is generally true, however, that an electronegative group (e.g., halogen or nitro) substituted at the 7-position markedly increases functional anxiolytic activity, although effects on binding affinity in vitro are not as dramatic. On the other hand, substituents at positions 6, 8, or 9 generally decrease anxiolytic activity. Other 1,4-diazepine derivatives in which ring A is replaced by a heterocycle generally show weak binding affinity in vitro and even less pharmacologic activity in vivo when compared to phenyl-substituted analogs. 44  SAR OF BENZODIAZEPINES Ring B A proton-accepting group is believed to be a structural requirement of both benzodiazepine and nonbenzodiazepine ligand binding to the GABA receptor, ~ interactions with a histidine residue that serves as a proton source in the receptor site. For the benzodiazepines, optimal affinity occurs when the proton-accepting group in the 2-position of ring B (i.e., the carbonyl moiety) is in a coplanar spatial orientation with the aromatic ring A. Substitution of sulfur for oxygen at the 2- position may affect selectivity for binding to GABA BZR subpopulations, but anxiolytic activity is maintained. Substitution of the methylene 3-position or the imine nitrogen is sterically unfavorable for antagonist activity but has no effect on agonist (i.e., anxiolytic) activity. Derivatives substituted with a 3-hydroxy moiety have comparable potency to non-hydroxylated analogs and are excreted faster. Esterification of a 3-hydroxy moiety also is possible without loss of potency. 45  SAR OF BENZODIAZEPINES Ring B Neither the 1-position amide nitrogen nor its substituent is required for in vitro binding to the BZR, and many clinically used analogs are not N-alkylated. Although even relatively long N-alkyl side chains do not dramatically decrease BZR affinity, sterically large substituents like tert-butyl drastically reduce receptor affinity and in vivo activity. Neither the 4,5-double bond nor the 4-position nitrogen (the 4,5- [methyleneimino] group) in ring B is required for in vivo anxiolytic activity although in vitro BZR affinity is decreased if the C=N bond is reduced to C–N. It is proposed that in vivo activity of such derivatives results from oxidation back to C=N. It follows that the 4-oxide moiety of chlordiazepoxide can be removed without loss of anxiolytic activity 46  SAR OF BENZODIAZEPINES Ring C The 5-phenyl ring C is not required for binding to the BZR in vitro. This accessory aromatic ring may contribute favorable hydrophobic or steric interactions to receptor binding, however, and its relationship to ring A planarity may be important. Substitution at the 4′-(para)-position of an appended 5-phenyl ring is unfavorable for agonist activity, but 2′-(ortho)-substituents are not detrimental to agonist activity, suggesting that limitations at the para position are steric, rather than electronic, in nature. Annelating the 1,2-bond of ring B with an additional “electron-rich” (i.e., proton acceptor) ring, such as s-triazole or imidazole, also results in pharmacologically active benzodiazepine derivatives with high affinity for the BZR. For example, the s-triazolo-benzodiazepines triazolam, alprazolam, and estazolam and the imidazo-benzodiazepine midazolam are clinically effective anxiolytic agents. 47 SAR OF BENZODIAZEPINES 48  SAR OF BENZODIAZEPINES Aromatic or heteroaromatic ring A is required for the activity that may participate in - stacking with aromatic amino acid residues of the receptor. An electronegative substituent at position 7 is required for activity, and the more electronegative it is, the higher the activity. Positions 6, 8, and 9 should not be substituted. A phenyl ring C at position 5 promotes activity. If this phenyl group is ortho or diortho (2,6) substituted with electron-withdrawing groups, activity is increased. On the other hand, para substitution decreases activity greatly. In diazepine ring B, saturation of the 4,5-double bond or a shift of it to the 3,4-position decreases activity. Alkyl substitution at the 3-position decreases activity substitution with a 3- hydroxyl does not. 49  SAR OF BENZODIAZEPINES The presence or absence of the 3-hydroxyl group is important pharmacokinetically. Compounds without the 3-hydroxyl group are nonpolar, 3-hydroxylated in liver slowly to active 3-hydroxyl metabolites, and have long overall half-lives. The 3-hydroxyl compounds are much more polar, rapidly converted to inactive 3-glucuronides, which are excreted in urine and thus are short-lived. The 2- carbonyl function is important for activity, as is the nitrogen atom at position 1. The N1-alkyl side chains are tolerated. A proton-accepting group at C2 is required and may interact with histidine residue (as a proton donor) in benzodiazepine binding site of GABAA receptor. Other triazole or imidazole rings capable of H-bonding can be fused on positions 1 and 2 and increase the activity. 50 EXAMPLES OF BENZODIAZEPINES 51 NB: some are useful as anxiolytics SAR OF BENZODIAZEPINES ~ SUMMARY 52 SAR OF BENZODIAZEPINES Regarding the SAR of sedative-hypnotic benzodiazepines, all five agents contain the 5-phenyl-1,4-benzodiazepine-2-one backbone required for GABA activity An electronegative 7-position chloro substitution as required on ring A. Similarly, all contain a pendant 5-phenyl ring (ring C) that is required for in vivo agonism and that can be substituted with ortho-electronegative halogens to increase lipophilicity as is the case with flurazepam, quazepam, and triazolam. Interestingly, para substitution on ring C leads to inactive benzodiazepines, suggesting that steric restrictions are 53 important at this site.  METABOLISM OF BENZODIAZEPINES Flurazepam is primarily metabolized by CYP3A4-mediated N- dealkylation and hydroxylation yielding active N1-desalkyl and N1-hydroxyethyl metabolites with elimination half-lives of 47 to 100 and 2 to 4 hours, respectively. Conjugation of N1-hydroxyethyl flurazepam in phase 2 reactions allows for urinary excretion, and this conjugate is the major urinary metabolite accounting for up to 55% of a single dose The long half-life of these metabolites explains the clinical findings that flurazepam exhibits faster sleep latency and decreases in total wake time following several days of use and why it is still efficacious for one to two nights following discontinuation of the parent. 54  METABOLISM OF BENZODIAZEPINES Quazepam is metabolized by microsomal CYP450 oxidases to yield 2- oxoquazepam, which is subsequently N-dealkylated to N-desalkyl-2- oxoquazepam. Both metabolites are pharmacologically active and have long durations. Both 2-oxoquazepam and N-desalkyl- 2-oxoquazepam can be further hydroxylated at the 3-position, yielding 3-hydroxy-2-oxoquazepam and 3- hydroxy-N-desalkyl-2-oxoquazepam, respectively. These hydroxylated metabolites are inactive and can be O-glucuronidated and excreted readily in the urine. Slow elimination of multiple active metabolites of both flurazepam and quazepam ~ residual hypnotic effects, including excessive daytime drowsiness, oversedation, and cognitive decline and confusion. 55 METABOLISM OF FLUZEPAM 56 METABOLISM OF QUAZEPAM 57 NONBENZODIAZEPINE GABA AGONIST Zolpidem, eszopiclone, and zaleplon, which are often referred to as the Z-drug are approved insomnia. Zolpidem (imidazopyridine) Eszopiclone (pyrrolopyrazine cyclopyrrolone) 58 Zaleplon (pyrazolopyrimidine)  MELATONIN RECEPTOR AGONISTS Melatonin is a neurohormone that is primarily synthesized in the pineal gland from its precursor serotonin. Increase in endogenous nighttime melatonin levels correlates with the onset of sleepiness The sleep-promoting effects of melatonin are due to agonism of both MT1 and MT2 receptors (MT1R, MT2R) (S)-Ramelteon ~ melatonin receptor agonist approved for insomnia and selectively binds to both MT1R and MT2R 59 THANK YOU FOR YOUR ATTENTION 60