Major tranquilizers (also known as antipsychotics or neuroleptics) are used to treat more severe mental disorders like schizophrenia and bipolar disorder. They work by blocking the neurotransmitter dopamine in the brain. There are two main classes - typical and atypical. Typical antipsychotics include phenothiazines (e.g. chlorpromazine), thioxanthenes, and butyrophenones. They are effective but have side effects. Atypical antipsychotics have fewer side effects and include clozapine, risperidone, and olanzapine. Minor tranquilizers are used for milder anxiety and include benzodiazepines like diazepam, alprazol
Slides are prepared as per INC Syllabus Unit IX Drugs used in nervous system and it is most benefited for B sc Nursing students and faculty of the subject
It is a anti- hypertensive drug. It is non-selective beta blocker drug. Hence it is beta blocker drug so it has many side effect.Not only Propranolol but also Timolol,Atenolol are beta blocker drugs.
Slides are prepared as per INC Syllabus Unit IX Drugs used in nervous system and it is most benefited for B sc Nursing students and faculty of the subject
It is a anti- hypertensive drug. It is non-selective beta blocker drug. Hence it is beta blocker drug so it has many side effect.Not only Propranolol but also Timolol,Atenolol are beta blocker drugs.
What is Psychosis? Types of Psychosis, Chemical Classification of Antipsychotic drugs, SAR of Phenothiazenes and Butyrophenones, Chemistry, IUPAC nomenclature, MOA and uses of antipsychotic drugs.
Here is an overview of Antipsychotics,starting from basic pathophysiology of Psychosis and Schizophrenia,breifing the Neuropharmacology and lastly introduction of drugs with special reference to side effects and clincal uses.
As a Social Work student specialized in Medical and Psychiatry, I was assigned to study and present on Psychotropic Drugs in class. Hope it helps you!
This contains introduction to psychotropic drugs, definitions, a brief history of psychiatric treatment, classification, characteristics of an ideal psychotropic drug as well as the references to my sources.
Introduction:
SEDATIVES CNS depressant drugs , reduce excitement & tension, & produce calmness & relaxation.
HYPNOTICS drugs that produce sleep similar to that of natural arousal sleep.
Both sedative & hypnotic action may reside in the same drug.
A small dose may act as sedative, whereas a large dose of the same drug may act as a hypnotic.
SAR of Benzodiazepine:
Presence of phenyl ring / pyridyl ring promotes sedative-hypnotic activity at C5-position.
If presence of electron withdrawing group like –Cl or –NO2 (Lorazepam, Clonazepam) at R2’ position, then sedative-hypnotic activity .
Presence of electron withdrawing group like –Cl,
-F, –NO2 at C7 position, activity.
Substitution at 6,8,9 position of carbon atom, activity.
Shifting of double bond present between –N4 & C5 or saturation of double bond activity.
R3 = alkyl group, activity & R3 = -OH or –COOH activity & R1 = -CH3 ,if larger group is present activity.
Sleep is mainly loss of consciousness. Sleep is an architectured cyclic process.
These drugs maintains the sleep-wake cycle.
Insomnia is a symptom & its proper treatment depends on finding the cause of sleeplessness. To treat this type of patient, use sedative-hypnotics.
High dose of the drugs may lead to coma or death.
This presentation contains a brief introduction of Adrenergic and cholinergic systems and their function in our body.
And a brief description of some adrenergic and cholinergic agents along with their mechanism of action along with their respective Structures.
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
2. Tranquilizer is a drug that is used to reduce anxiety, fear, tension, agitation,
and related states of mental disturbance.
Tranquilizers fall into two main classes, major and minor.
Major tranquilizers, which are also known as antipsychotic agents,
or neuroleptics, are so called because they are used to treat major states of
mental disturbance in schizophrenics and other psychotic patients.
Minor tranquilizers, which are also known as antianxiety agents,
or anxiolytics, are used to treat milder states of anxiety and tension in
healthy individuals or people with less serious mental disorders.
Antipsychotics, also known as neuroleptics, are a class of
medication primarily used to manage psychosis (including delusions,
hallucinations, paranoia or disordered thought), principally in
schizophrenia but also in a range of other psychotic disorders.
Tranquilizers
4. The principal minor tranquilizers are the benzodiazepines, among which are
diazepam (Valium), chlordiazepoxide (Librium), and alprazolam (Xanax).
These drugs have a calming effect and eliminate both the physical and
psychological effects of anxiety or fear.
Benzodiazepines’ mechanism of action is enhancing the action of the
neurotransmitter gamma-aminobutyric acid (GABA), which inhibits anxiety
by reducing certain nerve-impulse transmissions within the brain.
Other, less commonly used minor tranquilizers include meprobamate
(Equanil, Miltown) and buspirone (BuSpar).
Minor Tranquilizers
7. [2-(carbamoyloxymethyl)-2-methyl-pentyl] carbamate
Tybamate
It is a prodrug for meprobamate
[2-(carbamoyloxymethyl)-2-methylpentyl] N-butylcarbamate
Minor Tranquilizers- Propandiol Dicarbamate Derivatives
Meprobamate
It was the best-selling minor tranquilizer for a time, but has largely been
replaced by the benzodiazepines
9. The individual drug can be studied :
Chlorpromazine*
Prochlorperazine
Trifluoperazine,
Thiothixene
Haloperiodol
Triperiodol
Oxypertine
Chlordizepoxide
Diazepam
Lorazepam
Meprobamate
10.
11. What are antipsychotic medications?
They are a range of medications that are used for some types of mental distress or
disorder - mainly schizophrenia and manic depression (bipolar disorder).
They can also be used to help severe anxiety or depression.
They all affect the action of a number of chemicals in the brain called
neurotransmitters – chemicals which brain cells need to communicate with each other.
Dopamine is the main neurotransmitter affected by these medications. It is
involved in how we feel: It is also involved in the control of muscle movements.
If parts of the dopamine system become overactive, they seem to play a part
in producing hallucinations, delusions and thought disorder.
The basic aim is to help feel better, without making one feel slowed down or drowsy.
Major Tranquilizers (Antipsychotics, or Neuroleptics)
12. •Antipsychotics, known also as neuroleptics, and major tranquilizers, not only
calm severly disturbed pyschiatric patients but also relieve them of the
symptoms of their disease.
•Like other psychoactive drugs, neuroleptics do not cure mental diseases, but
rather treat only their target symptoms such as hallucinations or manias.
•Neuroleptics usually do not shorten the duration of psychotic phasis in
schizophrenia, but they do decrease the severity of mania and depressions.
•Contrary to the effect caused by hypnotic and sedatives, they do not cloud
consciousness or depress vital centers.
Antipsychotics
13. • A class of antipsychotic drugs first developed in the 1950s
• Commonly used but not the best and not very selective
Examples:
Phenothiazine compounds
Thioxanthene compounds
Butyrophenone compounds
Atypical Antipsychotics
•Also known as second generation antipsychotics
•Less side effects (Parkinson like), more selective
Examples:
Clozapine
Risperidone
Olanzapine
Ziprazidone
Quetiapine
Amisulpride
Antipsychotics
Typical Antipsychotics
15. The basic types of Antipsychotics are the phenothiazines, thioxanthines,
butyrophenones, clozapine, and rauwolfia alkaloids.
The phenothiazines are the most widely used of these and include the drug
chlorpromazine.
They are thought to work by blocking the neurotransmitter dopamine in the brain.
This leads to a reduction of psychotic symptoms but can also result in unwanted
side effects
The butyrophenones, chief among which is haloperidol (Haldol), are similar
to the phenothiazines.
Another drug, clozapine, whose exact mode of action remains unclear
relieves schizophrenic symptoms in some patients who are not helped
by phenothiazines.
Clozapine lacks the side effects of the phenothiazines but tends to induce
an infectious disease known as agranulocytosis.
The rauwolfia alkaloids, such as reserpine, are no longer in common use.
Antipsychotics
16. Mechanism of Action:
The mechanism of action of antipsychotic drugs are only partially known.
Although the antipsychotic drugs represent a wide variety of chemical
structures, their pharmacological and clinical activities are remarkably
similar.
The theory that most antipsychotic agents act as antagonists at
pre- and postsynaptic dopamine receptors, that is, by blocking
dopamine from binding to its receptor sites.
Antipsychotics
17. PHENOTHIAZINE DERIVATIVES
First synthesized in 1950, chlorpromazine was the first drug developed with
specific antipsychotic action, and would serve as the prototype for the
phenothiazine class of drugs.
Phenothiazine derivatives are chemically characterized by a lipophilic fused
tricyclic system (the phenothiazine nucleus) linked through the nitrogen atom of
the central ring to a hydrophilic aminoalkyl substitutent (the tertiary basic side
chain).
R2N
R1
S
H 1
5
S
2
3
46
7
8
9 10N
Chemical Abstract system
Chlorpromazine
Antipsychotics
20. PHENOTHIAZINE DERIVATIVES
Structure-Activity Relationships
It is postulated that phenothiazines interact with dopamine
receptors at three distinct sites, A, B, C. The order of
importance in terms of structure activity is B C A.
XYN
R2
R3
Z
R1
Site A Site B
Site C
The pendent amine functionality
(Site A)
Intervening alkyl chain between the
central ring and the terminal amino
group (Site B)
A tricyclic ring system with six- or
seven-membered central ring (Site C)
Y=N, X=S
21. PHENOTHIAZINE DERIVATIVES
Structure-Activity Relationships
SITE B
•A three carbon atom chain is needed for optimum neuroleptic
activity
•This alkyl group should be bonded to a nitrogen atom
•A substituent at 2-position of this 3 carbon atom chain affects
activity. Whe R1 is a H atom the activity is optimal.
•Whereas small alkyl substituents such as methyl are tolerated at
the C2 carbon, larger substituents (for example R1: phenyl,
dimethylamino) that restrict the free rotation decrease neuroleptic
potency.
XYN
R2
R3
Z
R1
SiteA Site B
Site C
Y=N, X=S
Triflupromazine
22. N
CH2
RH
C
N CH2
CH3 N
S
SITE C
•The phenothiazine ring is not planar. For example, the angle between the
two phenyl planes is 159o in chlorpromazine and 141o in perphenazine.
•Phenothiazine ring is not necessary for neuroleptic activity. Other planar
tricyclic systems like thioxanthenes are active.
•Substituents at 2-position (X) of the phenyl ring improve activity. Electron
withdrawing substituents such as halogens, methoxy, acetyl, trifluoromethyl
increase activity.
• Substituents at 1, 3, 4-positions decrease activity.
X
ABölgesi B Bölgesi C Bölgesi
N
2
3
4
5
S
6
7
8
9 110
H
Chemical Abstract system
Site A Site B Site C
Structure-Activity Relationships of Phenothiazines
23. SITE A
Nature of the amino group
•The size and nature of the basic amino group has considerable influence on the
behavior of the phenothiazine neuroleptics, because the molecule has to fit into a
narrow space.
•A tertiary amine has optimal activity; presence of alkyl groups larger than methyl
or replacing methyl groups with hydrogen atoms decrease activity.
•On the other hand, if the nitrogen is part of a heterocyclic ring (such as in N-
methylpiperazine and piperidine compounds), neuroleptic potency may not be
reduced. The effective size of the piperazine ring for instance, is smaller than that
of the diethylamino group.
Structure-Activity Relationships of Phenothiazines
XYN
R2
R3
Z
R1
SiteA Site B
Site C
Chlorpromazine
24. PHENOTHIAZINE DERIVATIVES
Synthesis:
•Heating of appropriate diphenylamine (or 3-substituted diphenyl
amine) with sulfur yields the desired phenothiazine ring
(Bernthsen method).
N
S
R1
H
N
H
R1
S
S
R1N
H
Cl CH2CH2 CH2 R2
N
S
R1
CH2CH2CH2 R2
NaNH2
Alkylation of phenothiazine ring with various amino alkyl halogens
by means of sodium amide results in desired phenothiazine
derivatives.
25. The synthesis begins with the reaction of 1,4-dichloro-2-nitrobenzene with
2-bromobenzenethiol. Hydrogen chloride is evolved as a by-product of this step and a
thioether is formed as the product.
In the second step the nitro group is reduced with hydrogen gas. Upon heating in
dimethylformamide (DMF) solvent, ring cyclization occurs.
The 2-chloro-10H-phenothiazine thus produced is combined with
3-chloro-N,N-dimethylpropan-1-amine in the presence of sodium amide base to
form chlorpromazine.
Synthesis of Chlorpromazine
26. Biotransformation of Phenothiazines Derivatives
Phenothiazines undergo extensive biotransformation which include
aromatic hydroxylation, N- , S- oxidation and N-delakylation. The
metabolites are excreted to a large extent as glucronides.
S
N Cl
2 2 2CH CH CH N
CH3
CH3
S
N Cl
HO
CH2 CH2 CH2 N
CH3
CH3
S
N Cl
Glu O
CH2 CH2 CH2 N
CH3
CH3
S
N Cl
O
CH2 CH2 CH2 N
CH3
CH3
S
Cl
O O
N
CH2 CH2 CH2 N
CH3
CH3
S
N Cl
HO
CH2 CH2 CH2 N
CH3
CH3
O
S
N Cl
Glu O
O
CH2 CH2 CH2 N
CH3
CH3
O
S
N Cl
CH2 CH2 CH2 N
H
CH3
27. Antipsychotics - Butyrophenones
Haloperidol, the most widely used classical antipsychotic drug in this class
Droperidol, often used for neuroleptanalgesic anesthesia and sedation in
intensive-care treatment
Benperidol, the most potent commonly used antipsychotic (200 times
more potent than chlorpromazine)
Haloperidol (Haldol)
4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidyl]
-1-(4-fluorophenyl)-butan-1-one
Droperidol (Innovar)
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6-
tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
Benperidol
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-
1,3-dihydro-2H-benzimidazol-2-one
28. Structure Activity Relationships of Butyrophenones
All butyrophenone derivatives displaying high antipsychotic activity have
the following general structure:
•p-fluorobutyrophenone skeleton is essential for neuroleptic activity.
•All potent compounds have a fluorine substituent in the para position of
the benzene ring. Replacing F with other groups like Cl-, Br-, -OCH3
decreases activity
F p
R2
4'
R3
1'
2' 3'
N
1 2 3 4
C CH2CH2 CH2
O
29. Structure Activity Relationships of Butyrophenones
•Replacement of the keto group by a thioketone group decreases
neuroleptic activity.
• Reduction of the keto group to alcohol decreases potency.
•Lengthening, shortening, or branching of the three carbon (propyl)
chain decreases neuroleptic potency.
•Variations are possible in the tertiary amino group without loss of
neuroleptic potency. Nitrogen atom is usually incorporated into a six
membered ring (piperidine, tetrahydropyridine, or piperazine), which
usually has another substituent in position 4.
•R2 group should be aromatic. R3 group helps with activity, could be a –
OH group as in the case of haloperidol.
haloperidol
F p
R2
4'
R3
1'
2' 3'
N
1 2 3 4
C CH2 CH2 CH2
O
30. Conditions:
i. Fluorobenzene, aluminum chloride, carbon disulfide, room temperature, 2 h,
ii. 4-(p-chlorophenyl)piperadine-4-ol, potassium iodide, toluene, 100 - 110 ºC
4-chlorobutanoyl chloride 1 was reacted with fluorobenzene in presence
of aluminum chloride using carbon disulfide as solvent at ambient temperatures to
give 4-chloro-1-(4-fluorophenyl)butan-1-one.
Heating this compound with 4-(p-chlorophenyl)piperadine-4-ol in presence of
potassium iodide as catalyst and toluene as solvent affords Haloperidol.
Synthesis of Haloperidol
31. •Structurally related to phenothiazine derivatives, they resulted from
isosteric replacement in chlorpromazine and analogs.
•Their pharmacological actions and adverse effects are very similar to
those of phenothiazine derivatives.
• Examples include chlorprothixene, flupentixol, and thiothixene.
1
2
3
45
6
7
8 9
10
S
Antipsychotics – Thioxanthene Derivatives
32. X
The structure-activity relationship of the thioxanthene mimic that of
the phenothiazines:
•The thioxanthene ring is also nonplanar: the angle between the two
phenyl planes is 142o in chlorprothixene, 150o in flupentixol, and 142o in
thiothixene.
Structure Activity Relationships of Thioxanthene Derivatives
34. 2-substituted-9H-thioxanthen-9-one is prepared by the reaction of 2-
mercaptobenzoic acid and 4-substituted bromobenzene and following
Friedel Crafts reaction in the presence of a strong Lewis acid catalyst (such
as aluminium chloride).
Then 2-substituted-9H-thioxanthen-9-one is combined with an appropriate
alkyl magnesium bromide to give 9-alkyl-2-substituted-9H-thioxanthen-9-ol.
Treatment with a dehydration agent gives the corresponding 9-propylidene
derivative.
SH
COOH
Br
R1
+ K CO2 3
S
COOH R1
PCl5/AlCl3
S
O
R1
BrMg CH2 CH2 CH2 R2 S
R1
HO CH2 CH2 CH2 R2
S
R1
CH CH2 CH2 R2
POCl3
H2O
Synthesis of Thioxanthene Derivatives
35. Neuroleptics having dopamine receptor-blocking properties are frequently
responsible for the development of movement disorders.
Atypical antipsychotics are newer antipsychotic agents that have a
pharmacological profile different from older or typical antipsychotic drugs.
They cause less extrapyramidal side effects compared to the older typical
antipsychotic drugs.
They are more effective in treatment-resistant patients and have a greater
efficacy to treat negative symptoms, compared to the typical antipsychotics.
The three most accepted atypical drugs are; clozapine, risperidone and
olanzapine
Atypical Antipsychotics
36. 8-Chloro-11-(4-methylpiperazin-1-yl)-
5H-dibenzo[b,e][1,4]diazepine
Risperidone (Risperdal)
2-methyl-4-(4-methyl-1-piperazinyl)-
10H-thieno[2,3-b][1,5]benzodiazepine
Clozapine is an medication used in the treatment of schizophrenia, and is also
sometimes used off-label for the treatment of bipolar disorder. It is the first of the
atypical antipsychotics to be developed.
Clozapine (Clozaril, FazaClo) Olanzapine (Zyprexa)
4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-
1-piperidyl]ethyl]-3-methyl-
2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one
Amisulpride (Amipride , Amival, Sulpitac)
5,6-dimethoxy-2-methyl-3-
[2-(4-phenylpiperazin-1-yl)ethyl]-
1H-indole
(RS)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-
5-ethylsulfonyl-2-methoxy-benzamide
Oxypertine (Equipertine, Forit)
Atypical Antipsychotics
37. Conditions:
i. Phosphoroxichloride, Dimethylformamide, chloroform, reflux, 2 h,
ii. N-methylpiperazine, dioxane, reflux, 4 h
Synthesis of Clozapine
3-chloro-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one was treated with
phosphoroxichloride in presence of dimethylformamide as catalyst using chloroform
as solvent to give 3,6-dichloro-11H-benzo[b][1,4]benzodiazepine.
Treatment of this with N-methylpiperazine in refluxing dioxane affords Clozapine.