1. Tranquilizers /neuroleptics
Anti-Psychotics
Tranquilizers /neuroleptics
Antipsychotics
AMD
AMD

2. Psychotic Disorders Behavioral disorder.
Defined as mental disorders in which the personality is severely altered and a person’s contact with reality is impaired.
Characteristics: delusions, hallucinations, odd behavior, and incoherent or disorganized speech
Causes: Traumatic Experience, Stressful Event, and Drug Use
“ a loss of contact with reality, usually including false beliefs about what is taking place or who one is (delusions) and seeing or hearing things that aren’t there (hallucinations)

3. Types of psychosis 1) Schizophrenic :
It is neurological as well as psychological disorder. So fundamental and characteristic distortions of thinking and perception.
2) Affective (mood) disorders (bipolar) :
Disorders in fundamental disturbance is a change in mood to depression associated by a change is the overall activity
3) Organic psychosis :
Mental disturbances caused by head injuries, alcoholism, or other kind of organic diseases.

5. Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction.

6. A Beautiful Mind
The 2001 Academy Award winning film A Beautiful Mind was based upon the life of John Nash, a U.S. mathematician who jointly won the Nobel Prize for Economics in 1994

7. Treatment Before Drugs Came into Play
Patients were kept isolated from everybody else.
Shock Treatment: consisted of twirling patients on a stool until they lost consciousness or dropping them through a trap door into an icy lake
Insulin-Shock Therapy: consisted injecting insulin into the patient until he or she became hypoglycemic enough to lose consciousness and lapse into a coma
Institutionalized

8. Anti psychotic drugs
Major tranquilizers because they tranquilize and sedate.
Neuroleptics- CNS depressants that do not generally cause a loss of consciousness by themselves.
Neuroleptics- cause neurolepsy, which is an extreme slowness or absence movement.
Eliminate the symptoms of psychotic disorders but they do not cure them.
Tranquilize the emotional expressions , aggressive and impulsive behavior and thus calms the mind with out inducing sleep.
Modest sedative activity, Low potential for lethality, Low abuse potential, non-euphoric, Anti-emetic

9. Mechanism of action
The psychoses associated with the presence of greater dopamine level than the normal level
Schizophrenia is considered due to the overproduction of dopamine
All antipsychotic drugs tend to block the D2 receptors in the dopamine pathways in the brain, so the normal effect of dopamine release in the relevant synapses is reduced.
The anti-psychotic drugs act by increasing metabolic rate of dopamine or blocking dopamine (D2) receptors. This results an increasing concentration of excitatory (acetylcholine) and decreasing concentration of inhibitory (dopamine) components.
Since anti psychotic drugs shift the balance in favor of acetylcholine. Hence all the anti psychotic drugs are always associated with extra pyramidal effect.
The superimposibility of the conformations of dopamine and phenothiazine derivatives blocks the dopamine receptors, because it possess 3 carbons in side chain separating two nitrogen's.
Only addresses the positive symptoms of schizophrenia

10. Major Receptor Targets of Current Drugs
Dopamine D2
Antagonism reduces positive symptoms
Serotonin 5-HT2A
Helps to reduce certain side effects
Fine-tunes dopamine output
Other receptors involved:
Dopamine D1, D3, D4, & D5
Serotonin 5-HT1A & 5-HT2C
Muscarinic M1
Adrenergic α1 & α2
Histamine H1

11. Types of antipsychotics
There are currently two main types of antipsychotics in use:
Typical antipsychotics-----Chlorpromazine
Atypical antipsychotics-----Clozapine
Others- Reserpine
A new class of antipsychotic drugs has recently been discovered, known as dopamine partial agonists. Clinical development has progressed rapidly on partial dopamine agonists, and one drug in this class (aripiprazole) has already been approved by the US FDA.

12. Typical antipsychotics
Dibenz-(1,4)oxazepine, Loxapine
Phenothiazine
Derivatives
Chlorpromazine
Diphenylbutylamine
Pimozide
Butyrophenone
Haloperidol
Thioxanthene, Thiothixene
Chlorprothixene
Atypical antipsychotics
Dibenz (1,4)thiazepine
Quetiapine
Benzisoxmole,
Risperidone
Thienobenz(l,4)azepinOlanzapine
Benzisothiazole, Ziprasidone
Dibenz(l,4)diazepine
Clozapine

13. Others Rauwolfia alkaloids: Reserpine, deserpidine
Diphenyl methane derivatives: Pipradrol, captodiame, Hydroxyzine, benactyzine.
Beta - Aminoketones : Molindone, Ondansetron.
Benzamides : Sulperide, Remoxipride.
Miscellaneous: Buspirone, Meprobamate, Tybamate.

14. Tricyclic Neuroleptics- Phenothiazine
First agent- chlorpromazine
Chlorpromazine index is used to test the biological potencies of newer compounds
Dissected into three substructures, 1) amine side chain (site A), 2) the diary1 heterotricyclic ring (site C), and the intervening alkyl chain (site B)
Distance between sites A and C is critical for neuroleptic activity, with a three carbon chain being optimal.
6-6-6 system
Chlorpromazine

15. Phenothiazines General Structure
Thioxanthenes
Phenothiazines
Ring with substituent is designated as “A” ring
More than 24 phenothiazine and the related thioxanthene derivatives are used in medicine, most of them for psychiatric conditions

16. Dopamine Receptor
Since dopamine is structural analog of norepinephrine the receptor area is probably similarly configured, that is
Anionic site on receptor to interact with the protonated nitrogen of dopamine
A flat, hydrophobic area that interacts with the phenyl ring and hydrogen bonding at specific areas around the phenyl ring to accommodate the ring hydroxyls
A two carbon distance between the anionic site and the ring site

17. Phenothiazine Binding to D2 Receptor
Protonatable nitrogen that can interact with the anionic site on the receptor
A phenyl ring to interact with the flat hydrophobic area of the receptor
The two carbon distance is attained through molecular bending of the side chain, which contains a three carbon bridge, toward one of the phenyl rings to approximate a two carbon distance
Ring geometry is also important in the binding of phenothiazines to their receptor

18. Antagonism vs Agonism
Phenothiazines interact with a variety of different receptors: Cholinergic, histaminergic, adrenergic, dopaminergic and serotonergic
All of these interact with their receptor in a similar mechanism which is basic nitrogen, hydrophobic area (an aromatic ring except for acetylcholine) and proper separation of the two functional groups. In addition there is some key hydrogen bonding that differs among the various species
In each case phenothiazines are antagonists and there are two possible reasons:
The bulk attached to the phenyl ring interferes with receptor perturbations resulting in an antagonistic effect rather than an agonistic effect
The g nitrogen may bind to the anionic site on the receptor but the bulky, hydrophobic ring structure may actually bind an allosteric site on the receptor effectively covering a portion of the receptor which would keep the agonist from binding

19. Phenothiazine General SAR
Substitution at positions 1 and 4 both decrease antipsychotic activity (position 1 > position 4)
Unsubstituted phenothiazines have weak antipsychotic activity.
Three carbon chain connecting nitrogen is required. Two or four carbon chain greatly decreases activity.
Branching on the side chain with large groups decreases activity.
Branching at the γ carbon is tolerated.
Position 2 is the best position for substitution.
Activity generally increases with the electron-withdrawing ability of the substituent.
Basic nitrogen substituents –tertiary amines provide optimal activity; secondary amines have decreased activity.
Significant increases in size from the dimethylamino group decrease activity.
Piperidine (thioridazine) and piperazine rings (fluphenazine) are allowed.
Addition of chain length on the N2 of the piperazine ring is proposed to increase receptor binding forces.
The tertiary amine is required for passage thru BBB, but the protonated ammonium species is the important form at the receptor.

20. Phenothiazine SAR Propyl Side Chain
Propyl is best, butyl is nearly inactive, ethyl has low activity. Compounds with ethyl chains often have antihistaminic activity.
Any substituent at the first position of the side chain decreases activity.
Substitution of a methyl at position 2 of the chain is OK. Large aliphatic substituents are not tolerated.
A larger range of substitutions are tolerated at position 3. The nitrogen is often included as part of a ring

21. Modification of X and the Tricyclic Nucleus
Phenothiazine SAR
Modification of X and the Tricyclic Nucleus
Highest activity is associated with an electron withdrawing, lipophilic substituent (halogen) at position 2.
A trend in activity changes can be seen with alterations in the identity of X; increasing lipophilicity and e- withdrawing increases activity.
Disubstitution of the ring decreases activity, ring cleavage is inactivating.
Replacing S with C, O, Se, etc. decreases activity. Replacing the nitrogen eliminates activity.
Compounds having larger central ring (Example: Imipramine (7 membered) and smaller central ring Example: carbazole (5 membered ring) are lack in antipsychotic activities and produce only antidepressant activity.)

22. Identity of Phenothiazine X and Effects on Potency
Phenothiazine SAR
Identity of Phenothiazine X and Effects on Potency
The order of potency for a “few” X substituent's are shown.
The most important are indicated by arrows, and Cl of course

23. Modification of Side Chain Amino Group
Phenothiazine SAR
Modification of Side Chain Amino Group
The highest activity is for 3° amines (pKa’s of 8-10).
Methyl R groups on nitrogen have greater activity than larger aliphatic groups..
The amino group can be part of a cyclic structure. The cyclic amines include pyrrolidine, piperidine, and piperazine. The piperazine substituent, in particular, generally increases potency.
Introduction of hydroxyl , methyl, hydroxy ethyl groups of piperidine and Piperazine moieties increase the potency.
N4-Piperazine substituents with phenyl ethyl, p – amino phenyl ethyl or estirified long chain fatty acids increases the activity.
Propyl dimethylamino side chain-(chlorpromazine)
Alkyl piperdinyl and pyrrolidinyl side chain- (thioridazine)
Propyl piperazine side chain- (prochlorperazine)

24. Potency Comparison Potency at the D2 receptors:
Given equal C2 substituents, ranked from most potent to least potent - Piperazine > Aliphatic > Piperidine
Of drugs on the market, however, the rank is - Piperazine > Piperidine > Aliphatic
Anticholinergic potency: Piperidine > Aliphatic > Piperazine
α Receptor antagonism: Aliphatic > Piperidine > Piperazine (This may be due to the fact that in order to get a good antipsychotic effect (D2 antagonism) large doses must be given and so the α receptor antagonism, although weak, is seen more)
Extrapyramidal side effects: Piperazine > Aliphatic > Piperidine (Low anticholinergic potency in the presence of strong D2 block)
Sedation: Piperidine > Aliphatic > Piperazine

25. Phenothiazine Metabolism- Major Routes
Cyp3A4
Glucuronidation and
excretion

26. Aliphatic Phenothiazine's
Chlorpromazine
Promazine
Triflupromazine
Piperidine Phenothiazine's
Piperazine Phenothiazine's
Fluphenazine
Mesoridazine
Thioridazine
Perphenazine

27. Thioxanthenes
Nitrogen atom in phenothiazine is replaced with a carbon atom which forms a double bond with the first carbon in the side chain.
Z isomer (cis isomer) is more active than E isomer (trans)
6-6-6 system
Chlorprothixine
X= CF3= Flupentixol
X= Cl= Clopentixol

28. Dibenz (1,4) oxazepine
Pinoxepine
Loxapine
Aminoalkylated derivatives of 6 : 7 : 6 compounds.
Unsubstituted aromatic compounds of this class showed almost exclusively as antidepressants

29. Dibenzthiepins Dibenzazepines
Octoclothiepine
Six times more potent than chlorpromazine in depressing spontaneous motor activity in the rotorod test
N-Methylpiperazinodibenzo(l,4)diazepines and related azepines, oxazepines and thiazepines, have all been tested clinically and have been shown to be effective in schizophrenic patients

30. Clozapine Manufactured in 1959 and first marketed in early 1960s
Withdrawn from market in mid-1970s after Finnish incident + agranulocytosis
Even so, clozapine reintroduced so as to treat people…
Resistant to typical neuroleptics
Compliant with blood monitoring
Improves delusions and hallucinations
Reduces the risk of suicide
Increases cortical dopamine (DA) and acetylcholine release
Various effects on glutamatergic system
Main clinical advantage = nil incidence of EPS

31. Olanzapine Quetiapine
Tienobenzodiazepine
Affinity for the following binding sites:
Dopamine (D1 – D4)
Serotonergics (5-HT2,3,6)
Muscarinics (sub-types 1 – 5)
Adrenergics (alpha2)
Histaminergics
New antipsychotic
Structurally related to clozapine but no need for blood monitoring
Predominant affinity for 5-HT2 in comparison with D2
Low incidence of EPS (less than 10%)

32. Butyrophenone Neuroleptics
Possess a tertiary amine at the fourth carbon of the butyral chain.
substituent at the 4th position of the aromatic ring
Butyrophenones are high-potency antipsychotics (potency refers not to effectiveness but rather to the ability to bind to dopamine receptors)
Haloperidol is the most common of the butyrophenones

33. Butyrophenone Neuroleptics

34. Butyrophenone SAR
For highest potency, X is always F. –OCH3 has the lowest potency, it reflects that an electron withdrawing group, not electron donating is optimal.
Shortening, lengthening, or branching of the propyl chain decreases potency
Reduction of carbonyl group and replacement of oxygen, sulphur or sulphone decreases the neuroleptic potency.
Y is usually C with two R groups, but may be N.
The amino group is in tertiary analogous to phenothiazines or part of six membered ring like piperidine, Piperazine for good neuroleptic activity
Replacement of six membered ring by larger, smaller or uncyclized diminishes neuroleptic potency
Neuroleptic potency is generally associated with 4,4- disubstituted piperidine. Substitution of 2 or 3 position of piperidine decreases potency.
The R1 group is variable and can enhance activity (R1 = OH in haloperidol)

35. Haloperidol: This is the prototype for this class
Haloperidol: This is the prototype for this class. One variation is to esterify the OH with decanoic acid to increase the duration.
Droperidol:- Strong sedative. In combination with Fentanyl (an analgesic) is given as a preanesthetic sedative Droperidol is also antiemetic which is important.
Trifluperiodol: Similar to Haloperidol

36. Comparisons Between the Two Classes of Drugs
Phenothiazines
Low potency
Are sedative
Block D2 receptors
Metabolism and removal of phenothiazines is complex and among the slowest of any group of drugs
Cause extra pyramidal symptoms
Butyrophenones
High potency
Non-sedative
Block D2 receptors
Metabolism and removal is quicker
Cause extra pyramidal symptoms

37. Benzamides
Discovery started with metoclopramide, an antiemetic agent showing D2 receptor antagonism.
2-methoxybenzamide substructure is important for activity
Benzamides with 2-pyrrolidinylmethyl side- chains were an area of intense investigation.
Optimal 1-substituents of the pyrrolidine ring were small alkyl, cycloalkyl, or benzyl.
In the case of alkyl substituents, the (S)- enantiomers were more active at blocking D receptors, whereas the reverse was true for the 1-benzylpyrrolidine derivatives
Removal of the N-substituent resulted in diminished activity.
Metoclopramide
Clebopride
Sulpiride

38. Ziprasidone Risperidone
Benzisoxazolic derivative with strong blocking affect on the D2 and 5-HT2 receptors
Stronger effect than haloperidol, but only when administered in doses > 8 mg/day
It has less extrapyramidal side effects due to no dopamine inhibitory effect in striatum and cortex
well absorbed orally and metabolized by hepatic CYP2D6 to 9-hydroxy active metabolite with a half-life of 22 hours.
Benzotiazolilpiperazine
More affinity for 5-HT2 than D2 receptor
It can also activate 5-HT1A in brain and partial D2 agonist activity in some selective cells which are important for these atypical antipsychotics
Provokes less EPS than conventional/typical antipsychotics
It has a half life of 6 hours with oral bioavailability ~60%

39. Aripiprazole One of the newest antipsychotics Lower incidence of EPS.
Partial Dopamine Agonist, Has high affinity for D2
Activates the receptor, but to a lesser extant than dopamine
Still causes an inhibitory effect
It is an arylpiperazine quinoline derivative with complex pharmacology.
Dopamine D2 and serotonin 5-HT1A & 5- HT2A/C receptor inhibitions are believed to be involved in its antischizophrenic therapy.
It has high affinity partial agonist effect to some D2 receptors depending on cell type, which explain its low extrapyramidal side effects.

41. Recent Findings Recent studies and meta-analysis have shown:
Current antipsychotics only treat positive symptoms
Some may even worsen negative and cognitive symptoms
Minimal improvement in efficacy in the past fifty years
Glumatergic Model
Function by blocking N-methyl-D-aspartate-type glutamate receptors (NMDARs)
Suggest a dysfunction of NMDARs in the glutamatergic system for schizophrenia
Greater potential of accounting for the multiple symptoms of schizophrenia
Drugs Developed to stimulate glutamate or NMDAR function

43. THANK YOU
Questions