Introduction , chapter 1 , Nahid Fatema thesis

Causes and biology of depression

1. Chapter - I
ABSTRACT
Depression occurs frequently which is a dangerous mood disorder with severe symptoms due
to which a person cannot eat, sleep and work properly. Among the types of neurotransmitters
Serotonin is the one of the most crucial neurotransmitters responsible for depression.
Two additional neurotransmitters that participate in depression are acetylcholine and
catecholamines, a class of neurotransmitters that include dopamine, norepinephrine, and
epinephrine (also known as adrenaline). As the first line of pharmacotherapy, selective
serotonin reuptake inhibitors (SSRIs) are now used to treat some of the most common
psychiatric issues, such as anxiety and depression.
In this study, the work is undertaken to discover and design new molecules which behave as
SSRI (selective serotonin reuptake inhibitors) for 5HT1A Receptors by conducting
pharmacophore-based studies by targeting protein (PDB ID: 7E2Z). Homology modelling of
the human 5HT7 was done using sequence information from the UniProt database (accession
code: P34969).
The readily available pyrazole analogues may reveal structural activity relationship (SAR)
hints and predicted potential therapeutic or detrimental effects. In order to develop
antidepressant medications, the active site of the enzyme produces tautomeric forms of
pyrazole. Various functional groups can be hyphenated to the pyrazole moiety as a central
motif. In future, novel analogues with unique pharmacokinetic, physicochemical and
pharmacodynamic properties be used as novel scaffolds.
1.2. INTRODUCTION
Depression is a psychological condition that is commonly diagnosed as a neuropsychiatric
disease with symptoms [1,2]. It has become a serious worldwide mental health issue and has
a substantial impact on the person's thoughts, behaviours, and feelings which include suicidal
thoughts, self-harm, lack of interest, depression, and disturbed sleep [1-4]. Depression may
cause cognitive changes such as slower processing speed, executive dysfunction, decreased
attention and concentration in impaired memory and learning [6]. Globally, there are
approximately 280 million people suffering from depression with a prevalence rate of 4.4%,
whereas in China prevalence of depression is approximately 4.2%. [7-9]. Depression has an
impact on the quality of life of patients, their families and the general people. Depression had
a significant impact on health-care costs [10]. Depression as a disorder has always been a
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focus of attention for researchers in India due to the morbidity. Several authors have
attempted to study its occurrence, nosological problems, and psychological risk factors
including life experiences. Several research studies have also attempted to address various
issues in elderly people and children.[11]
Depression is the most common mental illness in the elderly population, according to studies
conducted in the community, outpatient, inpatient, and nursing homes [12]. The most
prevalent mental illness was neurotic depression followed by manic-depressive psychosis,
anxiety, and depression.
A greater risk of psychiatric morbidity reported in those people who were economically,
socially, and educationally backward [13]. The high rate of morbidity among widowed
individuals was another significant discovery [14]. Epidemiology of depression in children
and adolescents 4–16-year age group have also been reported [15]. The rate of treatment of
mental health for the children (0-14 years) is increased from 2 to 13.49%. The literature
survey also reveals that 11% of women have been affected by post-natal depression during
and after pregnancy [16].
According to the 2015–16 National Mental Health Survey (NMHS) Every sixth Indian needs
mental health care.
VARIOUS REASONS SUCH AS EMOTIONAL (IRRITABILITY, DEPRESSED MOOD,),
SOMATIC (SLEEP, APPETITE, LIBIDO) FUNCTIONAL DISORDERS (SLOWED
SPEECH AND MOVEMENT, SUICIDAL THOUGHTS, LEARNING, MEMORY, AND
ATTENTION DEFICITS) LEADING DISABILITY IN THE GENERAL POPULATION
[17].
1.3. Types of mood disorder
The two main type of disorders are.
1.3.1. Major Depressive Disorder (MDD)
Depression actually refers to both a temporary emotional state that almost everyone
experiences at some point in their lives and a biobehavioural syndrome or clinical syndrome
known as Major Depressive Disorder (MDD) [19]. (MDD) is the term usually used when
someone refers to clinical depression. MDD is distinguished by different key characteristics
such as persistently low mood occurs in a person who has a history of mania, this is a form of
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bipolar disorder (previously termed Manic-Depressive Illness) [20]. Depression affects nearly
280 million people worldwide [8]. During the COVID-19 pandemic, the number of cases has
increased [18].
The earlier etiological theories of MDD primarily focused on monoamines. Many studies
have been conducted on the potential role of serotonin in MDD. Medication like selective
serotonin reuptake inhibitors (SSRI) have wide therapeutic benefits for depression [22,23].
Deficits in the transmission of serotonin, including reductions in serotonin (5-
hydroxytryptamine, 5-HT) neurons and their projections, and also increases in 5-HT
autoinhibition, have been related in pre-clinical and clinical research to MDD and decreased
antidepressant response [24-36]. MDD is not a condition that only impacts adults and older
people. A significant percentage of patients experience their initial symptoms of MDD in
their early adolescent and teenage years also.
1.3.2. Persistent Depressive Disorder (PDD)
Dysthymia, also known as persistent depressive disorder (PDD), it is a type of chronic
depression that lasts for minimum two years [37]. It ranges from mild to severe. Though the
symptoms are not as severe as those of major depression, they are long-lasting and
widespread. It includes symptoms such loss of interest and pleasure, as sadness, anger and
irritability. Guilt, low self-esteem, difficulty falling or staying asleep, sleeping excessively,
feelings of hopelessness, fatigue and lack of energy, changes in appetite, and difficulty in
concentrating can also be seen. [38-46].
1.4. Biological Factors for depression
Depression's common biological causes are strongly linked to abnormalities in the transport
of certain key neurotransmitters (chemical messengers in the brain). Serotonin is one of these
neurotransmitters [48,49]. Serotonin is possibly the most important neurotransmitter in
depression [50]. It is important for feelings of well-being, among other things. Serotonin
imbalances in the brain can lead to depression and other mood disorders [51]. Other
Neurotransmitters Acetylcholine and catecholamines, a group of neurotransmitters that
includes dopamine, norepinephrine, and epinephrine are two other neurotransmitters that may
be involved in depression (also called adrenaline) [52,53]. Common neurotransmitters and
their classifications have been summarized in Figure .1.1.
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Figure 1.1. Neurotransmitters and their classifications.
1.5. Medications
Medication like antidepressants is commonly used.
1.5.1. Antidepressants
Antidepressants are drugs that are widely used to treat depression. They could help your brain
use certain chemicals that controls mood or stress better [54]. Antidepressants are classified
according to how they affect the chemistry of the brain. Although antidepressants within a
category share the same side effects and mechanisms of action, variations in their molecular
structure can impact the drug's absorption, distribution, and tolerability in various people [55-
57].
1.6. Mode of action of Antidepressants
Learning about receptors, agonists, and antagonists is important to understand the amazing
mechanics of drugs [58,59].
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1.6.1. Receptors
Receptors are protein molecules found on the cell membrane in the human body. Outside the
cell, they receive signals (chemical information). Other molecules, such as hormones,
neurotransmitters, and drugs, provide this information. Ligands are molecules found inside
the body that bind to the receptors, causing that cell and sometimes other cells to respond.
Consider ligands to be keys that fit into specific locks, that are receptors [60-63].
1.6.2. Agonist drugs
These drugs stimulate the receptors to which they bind. This bond has the ability to either
raise or decrease cellular activities. These drugs have a similar structure to natural agonists
found in the human body [64,65]. They imitate natural agonists and activate receptors which
results in the desired behaviour or, in some cases a much relatively strong action. In other
words, an agonist is a key that happens to fit into a lock (the receptor) and unlocks a door
(produces a chemical reaction or cellular effect). The main key is the natural agonist, but
other keys (agonist drugs) can be designed to achieve the similar effect [66-70].
1.6.3. Antagonist
An antagonist is the substance that inhibits or opposes the action of an agonist drugs that bind
to the receptors, preventing natural agonists in the body from binding [71]. In other words, an
antagonist works by preventing an agonist from acting. To use the lock and key analogy a
cell is bound by an antagonist, which keeps agonists from properly attaching to the cell
receptor. As a result, the agonists lose their effectiveness [72,73].
1.7. How Antidepressants Functions
This is believed that three fundamental compounds, referred to chemically as monoamines,
are involved in mood regulation. They primarily function as neurotransmitters, sending nerve
signals to their corresponding receptors in the brain [74].
1.7.1. Dopamine
It is a neurotransmitter that is essential for decision-making, motivation, arousal, and pleasure
and reward signalling [75-76].
1.7.2. Norepinephrine
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These factors influence alertness and motor control in response to stress, as well as helping to
regulate blood pressure and heart rate [77].
1.7.3. Serotonin
This is a neurotransmitter that controls mood, appetite, sleep, memory, social behaviour, and
desire [78]. The accessibility of these neurotransmitters within the brain is distinctively low
in people suffering from depression. Antidepressants work by enhancing the availability of
one or more of such neurotransmitters in various ways [79,80].
1.8. Five major classes of antidepressants.
1.Selective Serotonin Reuptake Inhibitors (SSRIs)
2.Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
3. Tricyclic Antidepressants (TCAs)
4. Monoamine Oxidase Inhibitors (MAOIs)
5. Atypical Antidepressants
1.8.1. Selective Serotonin Reuptake Inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs) are now used as the first line of
pharmacotherapy to treat some of the most prevalent psychiatric diseases, such as depression
and anxiety [81,82]. Presynaptic inhibition is the therapeutic effects of SSRIs and other
antidepressants are in part due to the increase in serotonin. This cause due to the serotonin
transporter (SERT) at the synaptic cleft in other words SSRIs exert action by inhibiting the
reuptake of serotonin, thereby increasing serotonin activity shown in Figure.1.2. For
numerous reasons, but especially because of their binding selectivity, SSRIs represented a
significant advancement in the treatment of depression. SSRIs have a substantially better
specificity for SERT than MAOIs and TCAs [83]. At the presynaptic axon terminal, the
serotonin transporter (SERT) is inhibited by SSRIs. When SERT is inhibited, more serotonin,
also known as 5-hydroxytryptamine or 5HT, is retained in the synaptic cleft and has the
ability to stimulate postsynaptic receptors for a longer amount of time.
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Figure. 1.2. Schematic diagram showing mechanism of action of SSRI’s.
Apart from their acknowledged efficacy in managing depression, selective serotonin reuptake
inhibitors (SSRIs) have demonstrated notable effectiveness in addressing a spectrum of other
mental health conditions. These include Generalized Anxiety Disorder (GAD), obsessive-
compulsive disorder (OCD), panic disorder, severe phobias such as Agoraphobia and Social
Phobia, Bulimia, and Post-Traumatic Stress Disorder (PTSD). The versatility of SSRIs in
managing these varied mental health challenges underscores their significance in psychiatric
care beyond depressive disorders.
1.8.1.1. Common SSRIs prescribed

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1.8.1.2. Adverse Effects
The following side effects of SSRI are:
Diarrhoea, feeling queasy or worried, feeling generally unwell, Loss of libido, Impaired
vision, Dizziness, difficulties getting or maintaining an erection in males,
1.8.2. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
SNRIs are typically used to treat depression. For those who have received ineffective care
from selective serotonin reuptake inhibitors, they may be a beneficial method of treatment
(SSRIs). Serotonin is the only chemical messenger that SSRIs affect [84-86]. Depression is
associated with low levels of serotonin and norepinephrine. It is well known that these
chemical messengers, or neurotransmitters, affect mood. Since serotonin is linked to positive,
contented emotions, it is frequently referred to as a "feel-good" molecule.[87]. Energy and
alertness are linked to norepinephrine. SNRIs are believed to help treat depression by
preserving the levels of these two chemical messengers in the brain. They achieve this by
blocking the entry of serotonin and norepinephrine into the cells that released them.
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1.8.2.1. Common SNRIs prescribed
1.8.2.2. Adverse Effects
The following side effects of SNRI are:
Nausea, Changes in appetite, Muscle weakness, Tremor, Agitation, Heart palpitations,
Increased blood pressure, Increased heart rate, Headache, Difficulty to urinate, Dizziness,
Insomnia, Sleepiness, Dry mouth, Excessive sweating, Constipation, Fluid Retention,
especially in older adults, an inability to maintain an erection or have an orgasm (in men)
1.8.3. Tricyclic Antidepressants (TCAs)
A class of medications known as tricyclic antidepressants (TCAs) was first introduced to the
market in 1959 as a pharmacotherapy for major depressive illness (MDD) [88]. Tricyclic
antidepressants function by interfering with around five different neurotransmitter routes.
Due to their capacity to impede their absorption in presynaptic terminals, serotonin and
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norepinephrine are more concentrated in the synaptic cleft. Physicians usually only prescribe
tricyclic antidepressants when all other medications fail to treat depression. Tricyclic
antidepressants help to keep once brain's serotonin and norepinephrine levels elevated, that
body naturally produces. Tricyclic antidepressants can lift the mood by preserving these in
the brain. [89-92].
Tricyclic antidepressants are used to treat depression, but they also have negative health
implications. They may interfere with the body's natural muscular movements related to
digestion and secretion. The molecule histamine, which is present throughout the body, is
also blocked by them. Drowsiness, blurred vision, dry mouth, constipation, and glaucoma are
a few side effects of histamine blocking. These could provide an explanation for some of the
more problematic side effects of these medications [93,94].
1.8.3.1. Common TCAs prescribed
1.8.3.2. Adverse Effects
The following are examples of TCAs side effects:
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Dry mouth, Dry eyes, Blurred vision, Dizziness, Fatigue, Headache, Disorientation,
Drowsiness, Constipation, Urine retention, Sexual dysfunction, Low blood pressure, Weight
gain (especially with amitriptyline, imipramine, and doxepin), Nausea
1.8.4. Monoamine Oxidase Inhibitors (MAOIs)
A class of drugs called monoamine oxidase inhibitors (MAOIs) are
used to treat depression [95]. They were first made available as depression medications in the
1950s. An enzyme called monoamine oxidase aids in the firing of neurons all over the body.
It is created in the liver and clears out neurotransmitters from the brain once they have
completed their tasks [96-98]. Neurotransmitters, which are molecules in the brain that enable
communication between brain cells, are a target of MAOIs. Low levels of the
neurotransmitter’s dopamine, serotonin, and norepinephrine collectively known as
monoamines are regarded to be the root cause of depression. These neurotransmitters are
eliminated by monoamine oxidase, a substance that occurs naturally in the body [99,100].
1.8.4.1. Common MAOIs prescribed:

1.8.4.2. Adverse Effects
The following side effects of MAOIs are:
Fatigue, Muscles aches, Nervousness, Insomnia, Reduced libido, Erectile dysfunction, Light
headedness, diarrhea, Appetite, Weight gain, Dry mouth, High blood pressure.
1.8.5. Atypical Antidepressants
Antidepressants classified as atypical antidepressants do not belong to any of the four main
categories of antidepressants. However, depending on the symptoms and whether a person is
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also dealing with other mental health issues in addition to depression, they may be utilised as
a first-line treatment. Atypical antidepressants work by changing the neurotransmitters, which
are chemical messengers that connect brain cells, to lessen
depression [101]. It is similar to majority of antidepressants, treat depression by ultimately
affecting changes in brain chemistry and communication in brain circuitry known to control
mood.
1.8.5.1. Common Atypical Antidepressants prescribed
1.8.5.2. Adverse Effects
Dry mouth, Dizziness or Light headedness, Insomnia, Constipation, Diarrhoea, Appetite,
Weight gain, Nausea.
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1.9. Serotonin(5HT) 5-Hydroxy tryptamine and G protein signal transduction
Despite the fact that serotonin (5-hydroxytryptamine, 5-HT) was discovered 60 years ago
[102]. The study of serotonin and its receptors persists to yield new biological observations
with medical implications in almost all major organ systems, including the cardiovascular,
pulmonary, gastrointestinal (GI), and genitourinary systems, as well as the central nervous
system (CNS) [103]. The brain serotonergic system is known to control a wide range of
physiological functions as well as various types of behaviour. The presence of a large number
of serotonin receptors allows serotonin (5-hydroxytryptamine or 5-HT) to be polyfunctional.
Serotonin was discovered as a monoamine neurotransmitter in 1949. [104]. The first stage
and operation in 5-HT synthesis is tryptophan hydroxylase [105]. Only serotoninergic
neurons in the brain contained this enzyme. It allows tryptophan to be converted into 5-
hydroxytryptophan, which is then decarboxylated onto 5-hydroxytryptamine (serotonin) by
aromatic L-amino acid decarboxylase [106] depicted in Figure.1.3.
Figure.1.3. Synthesis of 5-hydroxytryptophan(5HT).
Neuronal activity has the capacity to control a variety of physiological processes. Emotion,
sleep quality, memory, pain, cognition, sexual behaviour, and mental illnesses are all aspects
of the body [106-108]. This natural neurotransmitter interacts with seven receptor families
(5HT1 to 5-HT7) and approximately fifteen receptor subtypes, G protein coupled
metabotropic receptors, though one member, the 5-HT3 receptor, is a ligand-gated receptor an
ion channel. Increasing number of 5-HT receptors has made it difficult to unravel the role of
5-HT receptor subpopulations due to the lack of suitable selective agents. The release or
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reuptake of 5-HT may result in a variety of pharmacological effects. [110]. Serotonin
involved in mood, fear, anxiety, and overall well-being. Serotonin imbalances, particularly
when compared to norepinephrine and dopamine. These are common causes of certain types
of depression. Antidepressants that block serotonin reuptake into serotonin neurons are
among the most commonly prescribed medications [111].
Currently, 14 subtypes of 5-HT receptors are recognized shown in Figure.1.4. The G protein-
coupled receptor (GPCR) superfamily comprises and 5-HT3 is categorized as an ion channel
receptor.
Figure .1.4. Types and subtypes of 5HT receptors.
1.9.1. The 5-HT1 receptor family
The 5-HT1 receptor's preliminary characterization arose from radioligand binding studies that
discovered binding sites for [3H]-5HT with strong affinity in rat cortex but low affinity for
spiperone. [112] This classification includes five receptor subtypes (5-HT1A, 5-HT1B, 5-HT1D,
5-HT1E, and 5-HT1F) that are structurally related in humans to 40-63%.
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Till date, there is no 5-HT1C receptor, it is renamed the 5-HT2C receptor. They mostly are (but
not always) associated with Gi/G0 proteins and inhibit cAMP production [113]. The
receptors of the 5-HT1 family have high amino acid sequence homology and all couple
negatively to adenylate cyclase via G-proteins.
1.9.1.1. 5-HT1A receptor:
The first receptor to be identified was the 5-HT1A receptor. By looking for homologous
sequences to the β2-adrenoceptor in a genomic library, the human and rat 5-HT1A receptors
were found. [114-116]. The rat 5-HT1A receptor (422 amino acids) has 89% homology with
the human receptor [117].
5-HT1A receptors are found in high density in the cerebral cortex, hippocampus, septum,
amygdala, and raphe nucleus, but they have also been found in small amounts in the basal
ganglia and thalamus [118]. Ligand has also been used for the in vivo labelling of 5-HT1A
receptors in mouse brain [119]. In limbic regions, 5-HT1A binding sites are highly
concentrated. The mesencephalic raphe nuclei (both dorsal and median raphe nuclei), the
lateral septum, the cingulate and entorhinal cortex, and the hippocampal region. In contrast,
there are hardly any 5-HT1A binding sites in the basal ganglia and cerebellum. [120]. In both
rat and guinea pig hippocampus tissue and cell-lines, the 5-HT1A receptor links negatively to
adenylate cyclase via G proteins(αi) [121]; 5-HT1A receptors function as postsynaptic
receptors and auto receptors in the brain. They control the creation of Adrenocorticotropic
hormone (ACTH) (but not prolactin), the suppression of the "discharge" of neurons, and the
regulation of behaviour and appetite [122]. Selective 5-HT1A receptor agonists include 8-OH-
DPAT, dipropyl-5-CT, and gepirone [123,124]. WAY 100 635 is the most potent 5-HT1A
receptor antagonists although NAD-299 appears to be somewhat more selective [125,126].
However, data suggest that as a group, these drugs have varying degrees of efficacy at 5-
HT1A receptors (pindolol > tertatolol > penbutolol=WAY 100 635; [127,128]. They most
likely have a significant impact on how anxiety develops. Studies using animals carrying a
knockout gene for this subtype of 5-HT1 receptor supported this observation. In numerous
experimental settings, the animals displayed heightened fear [129]. Additionally, 5-HT1A
antagonists (such as gepiron and buspiron) are being utilised or developed to treat anxiety and
depression. The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the
treatment of depression is increased by 5-HT1A receptor antagonists and the beta-blocker
pindolol [130]. While 5-HT1A drugs' depressive effects may predominantly give postsynaptic
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5-HT1A receptors, their antianxiety effects may primarily provide presynaptic somatodendritic
5-HT1A receptors (resulting in lower release of 5-HT in terminal regions) [131]. Anti-
aggressive behaviour is displayed by several 5-HT1A agents, and Nonviolent suicide victims
exhibited a much greater compared to controls and violent suicides, according to a study of
the density of 5-HT1A receptors in the frontal brain of suicide victims [132]. In some parts of
the brain, alcohol consumption is also linked to a reduction in the density of 5-HT1A receptors
[133].
1.9.1.2. 5-HT1B receptor
The 5-HT1B receptor was first described as a Low affinity for spiperone [3 H]-5HT binding
site in animal brain tissue [134]. The 5-HT1B binding site was found in high levels in rodents
(rat, mouse, hamster). 5-HT1B receptors have an impact on behaviour and presynaptic
inhibition in the central nervous system [135]. They do, however, also show signs of vascular
effects, including pulmonary vasoconstriction. There are 5-HT1B receptors in various areas of
the human brain. The striatum, frontal cortex, and basal ganglia contain the highest
concentrations. In the substantia nigra of rats and calf’s, a receptor with 5-HT1B receptor
pharmacology and a negative coupling to adenylate cyclase has also been discovered
[136,137].
At the 5-HT nerve terminal, the 5-HT1B receptor acts as a 5-HT autoreceptor. [138].
Depending on where it is located, the receptor has different functions; in the frontal cortex, it
is thought to function as a terminal receptor and prevent the release of dopamine. The 5-HT1B
receptor is believed to function as an autoreceptor, preventing serotonin from being released
in the striatum and basal ganglia. The modulation of additional neurotransmitters such
acetylcholine, glutamate, dopamine, norepinephrine, and aminobutyric acid is carried out by
5-HT1B receptors in a secondary function. This subtype was discovered in arteries throughout
the body, including the brain [139].
Mice that have 5-HT1B gene knockouts exhibit increased aggressiveness and a greater liking
for alcohol [140]. Agonists (such as dihydroergotamine, zolmitriptan, naratriptan, and
rizatriptan) are utilised or being researched. Beyond its ability to treat migraines, 5-HT1D/1B
agonists have been found to have a variety of additional effects, such as prokinetic effects on
the gastrointestinal tract, role in the treatment of antiplatelet effects, autism, etc [141].
1.9.1.3. 5-HT1D receptor
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A novel 5-HT1 receptor (5-HT1Dα), which is now referred to as the 5-HT1D receptor, was
discovered during the search for gene sequences with 5-HT1 homology. In addition to being
located in the heart, where they regulate serotonin release, 5-HT1D receptors function as
autoreceptors in the dorsal raphe nuclei [142]. Movement and anxiety are regulated by 5-
HT1D receptors in the central nervous system [143]. However, nothing is known about the
clinical importance of 5-HT1D receptors. Although it has been suggested that these receptors
may play a role in anxiety, depression, and other neuropsychiatric illnesses, this has mostly
remained unproven. It has been demonstrated, for instance, that GR127935 blocks the impact
of antidepressants in the mouse tail suspension test thanks to the presence of 5-HT1D
antagonists [144].
1.9.1.4. 5-HT1E receptor:
In radioligand binding tests, [3 H]-5-HT was discovered to bind to the 5-HT1E receptor in the
presence of inhibitors for other 5-HT1 subtypes [145,146]. Research on the 5-HT1E receptor
and its effects on neurons has not been conclusive. Research suggests that the 5-HT1E
receptor plays a significant physiological role in humans. This is the cells that consistently
express them shows that the receptor is negatively linked to adenylyl cyclase. It has been
demonstrated that 5-HT causes forskolin-stimulated cAMP accumulation to be inhibited by
Gi at low concentrations, but it also causes cAMP accumulation to be potentiated at greater
concentrations, mostly due to coupling to Gs [147].
1.9.1.5. 5-HT1E receptor:
The 5-HT1F receptor is significantly homologous to 5-HT1B, 5-HT1D, and 5-HT1E receptors
sharing similar structural properties, like resistance and seven transmembrane regions [148].
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It shares a moderate level of transmembrane homology with the 5-HT1E (70%), 5-HT1D (63%),
5-HT1D (60%), and 5-HT1A (53%). Despite having similarities to 5-HT1E receptors, 5-HT1F
receptors have a high affinity for 5-methoxytryptamine and several ergotamine derivatives.
The cloned human 5-HT1F receptor links to adenylyl cyclase inhibition [149]. The
nonselective 5-HT antagonist methiothepin totally blocked the antagonistic effects of 5-HT
and appeared to be competitive [150]. 5-HT1F receptors, are found in uterine and coronary
arteries leading to vascular contraction [160]. There are distributional parallels with 5-HT1D
receptors, despite the restricted appearance of distribution in the brain [161].
1.9.2. 5-HT2 receptors:
Three receptor subtypes, 5-HT2A, 5-HT2B, and 5-HT2C, are included in the 5-HT2 receptor
family. Three subtypes of this class—5-HT2A, 5-HT2B, and 5-HT2C show 46–50% structural
homology, are ideally connected to the Gq11 protein, and increase the intracellular Ca
2+
concentration as well as inositol trisphosphate hydrolysis These receptors are comparable in
terms of their molecular structure, pharmacology, and signal transduction mechanism [162].
5-HT2A may also have an inhibitory effect on some regions, including the visual cortex and
the orbitofrontal cortex, it is the major excitatory receptor subtype among the G-protein
coupled receptors for serotonin (5-HT) [163].
1.9.2.1. 5-HT2A receptor
There are several central and peripheral tissues that express the 5-HT2A receptor. Smooth
muscle contraction is caused by 5-HT2A receptors. Additionally, serotonin exposure was
linked to enhanced capillary permeability and platelet aggregation (perhaps as a result of this
receptor subtype being activated) [164]. 5-HT2A receptors are mostly found in the crust,
claustrum, and basal ganglia of the CNS. Evidence suggesting 5-HT2A receptor stimulation
activates a metabolic cascade that changes the expression of a variety of genes, including
brain-derived neurotrophic factor (BDNF), is currently of interest [165].
1.9.2.2. 5-HT2B receptor
The smooth muscles in the fundus of the stomach contract when the 5-HT2B receptor is
activated. The cerebellum, lateral septum, hypothalamus, and medial amygdala all showed
signs of 5-HT2B immunoreactivity [166]. Additionally, the 5-HT2B receptor system induces
longitudinal muscular contraction in the human colon and endothelium-dependent relaxation
in isolated rat veins [167]. Furthermore, activating the 5-HT2B receptor in mouse fibroblasts
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results in the activation of MAP kinase, which has a mitogenic effect. [168].SB 200646, a
developed antagonist of 5-HT2B receptors, may have clinical use in the management and
prevention of migraine [169]. It appears that this receptor is also found in heart valves, which
suggests that the valvulopaties reported in patients taking dexfenfluramin-containing appetite
suppressants may be caused by this receptor [170]
1.9.2.3. 5-HT2C receptor
The understanding of the 5-HT2C receptor's activity is still limited because there aren't any
specific ligands for it. Because it inhibits 5-HT2C receptors, the 5-HT2C antagonist
agomelatine works as an effective antidepressant by raising dopamine and norepinephrine
levels in specific brain regions [171]. Fluoxetine and other SSRIs indirectly boost 5-HT2C
activity by raising serotonin levels in synapses. On the other hand, several atypical
antipsychotics partially inhibit 5HT2C receptors. Fluoxetine does function as a direct 5HT2C
antagonist in addition to decreasing serotonin reuptake [172]. 5-HT2C receptors may also be
involved in the initiation of migraine attacks based on a significant correlation between
binding affinity and migraine prophylactic activity [173].
1.9.3. 5-HT3 receptor
The 5-HT3 receptor is an ion channel that is ligand-gated at the molecular level [174]. 5-HT3
receptors are present in both peripheral and centrally derived neurons. Presynaptic nerve
terminals also contain 5-HT3 receptors, which are supposed to mediate or regulate
neurotransmitter release. There are five subunits in it. Preclinical research suggests that 5-
HT3 antagonists may improve memory and be helpful in treating dementia, pain, sadness, and
anxiety. Lastly, research suggests that 5-HT3 antagonists may lessen the behavioral effects of
stopping long-term treatment with drugs of abuse, such as amphetamine, alcohol, nicotine,
and cocaine. [175].
1.9.4. 5-HT4 receptor
In cultured mouse colliculi neurones and guinea pig brain, first identified the 5-HT4 receptor
using a functional assay. It stimulated adenylate cyclase activity. When the 5-HT4 receptor is
active, the pig's oesophagus, colon, and ileum contract, and the ileum releases acetylcholine.
There are currently seven distinct 5-HT4A-H receptor variants. It differs in the sequence of the
C-terminal segment. A growing number of reports have indicated that activation of central 5-
HT4 receptors facilitates cognitive performance [176-181]. Considerations that 5-HT4
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receptors involved in the reward system and may affect self-administration behaviour are
made because of the nucleus accumbens due to high density of 5-HT4 receptors [182].
Mosapride, metoclopramide, renzapride, and zacopride are examples of 5-HT4 agonists that
also function as 5-HT3 antagonists. It is not feasible to consider these molecules as highly
selective.
1.9.5. 5-HT5 receptor
Two functional 5-HT5 receptor subtypes, 5-HT5A and 5-HT5B, have been found in rodents.
The pharmacological function of 5-HT5 receptors is still largely unknown. It has been
speculated that they may play a role in brain development, anxiety, depression, learning,
memory consolidation, and motor control based on their location [183]. Also, 5-HT5A
receptors may be involved in the regulation of astrocyte physiology by neurons in relation to
gliosis. Some CNS pathologies, such as Down syndrome, Alzheimer's disease, and some
drug-induced developmental deficits, may be caused by disruption of 5-HT neuron-glial
interactions [184].
1.9.6. 5-HT6 receptors
There are two 5-HT6 receptor variants have been described. 5-HT6 receptor, which has 440
amino acid residues, is mainly found in limbic and extrapyramidal cerebral zones. Certain
antidepressants and atypical antipsychotics point to a potential connection between the 5-HT6
receptors and specific mental disorders. 5-HT6-selective antagonists may be helpful in
treating deficits in memory and anxiety [185].
1.9.7. 5-HT7 receptors
There are 445 amino acids in the human 5-HT7 receptor. and increases adenylyl cyclase
activation through the Gs protein pathway. Antidepressants with a high affinity for 5-HT7
receptors include risperidone and clozapine are atypical antipsychotics. Chronic
antidepressant use causes these receptors to be down-regulated, whereas acute (but not
chronic) stress causes them to become more active [186]. 5-HT7 receptor antagonists reflect
the effects of selective serotonin reuptake inhibitors (SSRIs) and may be used to treat
depression and sleep disturbances [187].
1.10. Serotonin:
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Among the monoamines, serotonin is special in that it functions through a variety of G
protein-coupled receptors and a single ligand-gated ion channel. It is clear that over the past
20 years, a wealth of new knowledge about the various 5-HT receptor types and subtypes, as
well as their properties, has become available. This results from two primary studies,
operational pharmacology with selective ligands and molecular biology are two methods.
Which roles some of the numerous subtypes play in health or disease are still unknown.
There are numerous connections between 5-HT receptors and disease, as shown by the
extensive list of drugs that target one or both receptors, with some also targeting multiple
receptors simultaneously. The system's complexity is probably even larger than suspected.
The results of this research may then be used to help create medications that have a suitable
profile for the target organ and the particular disease. However, the variety of receptors
described above leads one to hypothesise that under physiological and pathological
circumstances. the status of the receptors may differ from patient to patient, which would
explain variations in responder rates to a particular drug. However, each 5-HT receptor
subtype listed in this chapter may have a different therapeutic potential.
1.11. Pharmacological activity of heterocyclic compounds and their
derivatives:
Heterocycles, commonly referred to as heterocyclic compounds, are organic chemical entities
characterized by a ring-like structure that incorporates one or more heteroatoms [195].
These compounds find extensive applications in various fields, including agriculture
(agrochemicals), medicine, and veterinary sciences. Additionally, they play essential roles in
copolymers, corrosion inhibitors, antioxidants, sanitizers, dyestuffs, and other industrial
products [196]. Currently, heterocycles are integral in the synthesis of numerous organic
compounds. Among these, nitrogen-containing heterocyclic compounds hold particular
significance, being crucial in physiologically active complexes, natural products, and
medicinal chemistry [197-199].
Researchers have not only focused on nitrogen-based heterocycles but have also exhibited a
strong interest in other varieties, especially those containing sulfur. Sulfur-containing
heterocyclic compounds form a substantial portion of FDA-approved medications and
therapeutically effective chemicals, [198,199] showcasing various biological activities such
as anti-diabetic, antibacterial, anticancer, antiviral, antimicrobial, anti-inflammatory, anti-
hypertensive, antimalarial, anti-Alzheimer's, and antifungal effects. 201]
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These sulfur-containing heterocyclic compounds have become indispensable in chemical
research, featuring prominently in natural products, medicines, and even food
flavoring[202,203]. Medicinal chemistry endeavors to enhance derivatives through ongoing
research [204]. The pyrazole ring, a vital component in rational drug development, has gained
widespread usage in both medical and industrial applications [205]. Serving as a privileged
structure found in diverse drug classes, the pyrazole moiety has stimulated the creation of
novel drug categories [206-208]. With its heterocyclic nitrogen-containing core, the pyrazole
moiety offers numerous targets and effects (refer to Figure 1). Existing pyrazole analogues
aid in establishing structure-activity relationships (SAR), providing insights into potential
therapeutic or adverse effects [209-211].
Monoamine levels are essential to the development of various psychiatric disorders, including
anxiety and depression [213]. In this context, inhibiting monoamine oxidase (MAO) stands as
a valuable assessment for evaluating the antidepressant properties of new drug candidates
[214]. The simplified synthetic routes and potential activities of pyrazole derivatives are
anticipated to inspire further chemical modifications for clinical applications [215]. Emerging
analogues, with distinct physicochemical, pharmacokinetic, and pharmacodynamic
properties, hold promise as research scaffolds in future endeavours, given the central motif of
the pyrazole moiety to different functional groups [216-220] Figure.1.5.
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Figure .1.5. Effects of pyrazole analogues on various cell.
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