chapter - 1 introduction to g-protein coupled receptors...
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CHAPTER - 1
INTRODUCTION TO G-PROTEIN COUPLED RECEPTORS AND THEIR
DRUG ACTION
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towards 5-HT6R. These molecules were synthesized with high purity and
in good yield. All the synthesized molecules are well characterized with
spectral data.
1.2 The medicinal chemistry:
Medicinal chemistry is an intersection of pharmacology and chemistry
involving design, synthesis and development of pharmaceutical drugs [6].
Medicinal chemistry involves the synthesis, identification and
development of new chemical entities (NCE) suitable for therapeutic use
[6, 7].
Fig: 1.1
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1.3 Receptors:
Receptor is a protein molecule which is located either in the
cytoplasm or on the plasma membrane of a cell [8]. A molecule which
binds to a receptor is called a ligand [9]. A huge number of these
receptors have been identified and are divided into three families [8]
defined by the mechanism used to transduce signal as a cellular
response (Fig: 1.1).
1.3.1 Channel-linked receptors:
Channel-linked receptors are also called LGICs [10]. Interaction of the
chemical signal with the binding area of the receptor causes the closing
or opening of an ion channel pore in another part of the same molecule
[10]. The resulting ion flux changes the membrane potential of the target
cell and in some cases, can also lead to entry of Ca2+ ions that serve as a
second messenger signal within the cell [10].
1.3.2 Enzyme-linked receptors:
Enzyme-linked receptors [11] are also having an extracellular binding
site for chemical signals. The intracellular domain of such receptors is an
enzyme whose catalytic activity is regulated by the binding of an
extracellular signal [11]. The most majority of these receptors are often
tyrosine kinases, protein kinases, which phosphorylate intracellular
target proteins, thereby changing the physiological function of the target
cells [11]. GPCRs regulate intracellular reactions by an indirect
5
mechanism involving an intermediate transducing molecule, called the
GTP-binding proteins.
1.3.3 Intracellular receptors:
Intracellular receptors [12] are activated by lipophilic or cell-permeant
signaling molecules and lead to the activation of signaling cascades that
produce new mRNA and protein within the target cell. When the
signaling molecule binds to the receptor, the inhibitory complex
dissociates to expose a DNA-binding domain on the receptor [12]. This
activated form of the receptor can then move into the nucleus and
directly interact with nuclear DNA, resulting in altered transcription [12].
1.3.4 Receptor agonists:
Agonist will bind and activate a receptor, showing full efficacy at that
receptor [13].
1.3.5 Receptor antagonist:
It is a type of receptor drug or ligand that does not show a biological
response itself upon binding to a receptor, but dampens or blocks
agonist-mediated responses [14].
1.4 G-protein coupled receptors (GPCRs):
GPCRs are also known as 7TM domain receptors [1]. GPCRs are
found only in yeast, choanoflagellates, eukaryotes and animals [2]. G-
6
proteins, short form for guanine nucleotide-binding proteins are involved
in second messenger cascades [15, 16]. GPCRs are two principal signal
Fig: 1.2
transduction pathways involving the Phosphatidylinositol signal pathway
and the cAMP signal pathway [15 - 17]. G-proteins are so called because
they function as "molecular switches," alternating between an active
guanosine triphosphate (GTP) and inactive guanosine diphosphate (GDP)
[18], ultimately going on to regulate downstream cell processes. The
GPCRs family transduces extracellular signals across the plasma
membrane, activating cellular responses through a variety of second
messenger cascades (Fig: 1.2, PKC and PKA signaling pathways) [19, 20].
These receptors provide rapid responses to a variety of stimuli, and are
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often rapidly attenuated in their signaling [19]. At the synapse, removal
of neurotransmitter or peptide signaling molecules is accomplished by
either reuptake or degradation. Desensitization of GPCRs occurs through
protein kinases that phosphorylate the GPCRs to turn off signaling [19].
Downstream protein kinases such as PKA and PKC turned on by GPCRs
signaling can phosphorylate the activated GPCRs and other GPCRs to
prevent further signaling [20].
1.5 Serotonin receptors:
The serotonin receptors are the target of a variety of pharmaceutical
substances, including many antipsychotics, antidepressants, anorectics,
antiemetics, gastroprokinetic agents, hallucinogens, entactogens and
Fig: 1.3
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antimigraine agents [5]. Molecular pharmacological properties, cloning,
second messenger coupling and amino acid sequence have led to the
identification of fourteen serotonin receptor (5-HTR) subtypes that can be
classified [21] into seven subfamilies (5-HT1-7) (Fig: 1.3) all of which are
GPCRs except for 5-HT3R a ligand-gated ion channel [21]. In particular,
the 5-HT1R are functionally coupled to Gi/Go, the 5-HT2R to Gq, and 5-
HT6R and 5-HT7R to Gs and thus activate cAMP [21].
1.5.1 5-HT1 receptors:
The 5-HT1R are subfamily of 5-HTR that are coupled to Gi/Go and
mediate inhibitory neurotransmission, including 5-HT1AR, 5-HT1BR, 5-
HT1DR, 5-HT1ER and 5-HT1FR. There is no 5-HT1CR, as it was reclassified
as the 5-HT2CR [21].
1.5.1.1 5-HT1A receptor:
The 5-HT1AR is found both postsynaptically and presynaptically [22].
8-OH-DPAT (I) [23] is a 5-HT1AR agonist. WAY-100,635 (II) [24] is a 5-
HT1AR antagonist.
1.5.1.2 5-HT1B receptor:
The 5-HT1BR acts on the CNS, where it induces presynaptic inhibition
& behavioural effects [25]. 5-HT1BR is identified in many parts of the
human brain. The major concentrations are found in the striatum, basal
ganglia and the frontal cortex. CP-94,253 (III) [26] is a 5-HT1B agonist.
AR-A000002 (IV) [27] is a 5-HT1B antagonist.
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1.5.1.3 5-HT1D receptor:
The 5-HT1DR acts on the CNS, and affects anxiety and locomotion
[28]. Frovatriptan (V) [29] is a 5-HT1DR agonist. BRL-15,572 (VI) [30] is a
5-HT1DR antagonist.
1.5.1.4 5-HT1E receptor:
The receptor is involved in the regulation of memory in humans due
to the high abundance of receptors in the hippocampus, frontal cortex
and olfactory bulb all of which are regions of the brain integral to
memory regulation [31]. Eletriptan (VII) [32] is a 5-HT1ER agonist.
Metitepine (VIII) [33] is a 5-HT1ER antagonist.
1.5.1.5 5-HT1F receptor:
The 5-HT1FR may provide an effective treatment for migraine without
cardiovascular side effects [34]. LY334370 (IX) [35] is a 5-HT1FR agonist.
1.5.2 5-HT2 receptors:
Three 5-HT2R subtypes (5-HT2A, 5-HT2B and 5-HT2C) show
considerable homology at structural, genetic and functional levels. 5-
HT2R mediate the actions of many drugs used in treating diseases such
as feeding disorders, schizophrenia, depression, perception, migraines,
hypertension, hallucinations, anxiety and gastrointestinal dysfunctions
[36].
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1.5.2.1 5-HT2A receptor:
The 5-HT2AR is a subtype of the 5-HT2R [37]. LSD (X) [38] is a 5-
HT2AR agonist. Ritanserin (XI) [39] is a 5-HT2AR antagonist.
1.5.2.2 5-HT2B receptor:
The 5-HT2BR regulates serotonin release via the serotonin transporter
and is important both to normal physiological regulation of serotonin
levels in blood plasma [40]. BW-723C86 (XII) [41] is a 5-HT2BR agonist.
RS-127445 (XIII) [42] is 5-HT2BR antagonist.
1.5.2.3 5-HT2C receptor:
The 5-HT2CR is one of the varieties of binding sites for serotonin.
Activation of this receptor by serotonin inhibits dopamine and
norepinephrine release in certain areas of the brain [43]. 5-HT2C
receptors significantly regulate mood, anxiety, feeding and reproductive
behavior [44]. Ro60-0175 (XIV) [45] is a 5-HT2BR agonist. SB-242084
(XV) [46] is a 5-HT2CR antagonist.
1.5.3 5-HT3 receptor:
The 5-HT3R is a ligand-gated ion channel that mediates fast
depolarizing responses and is apparently selective for the monovalent
cations Na+ and K+ and for the divalent ones Ca2+ and Mg2+ [47].
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Chlorophenylbiguanide (XVI) [48] is a 5-HT3R agonist. Granisetron (XVII)
[49] is a 5-HT3R antagonist.
1.5.4 5-HT4 receptor:
The 5-HT4R provided a mechanism of action for the gastric prokinetic
drugs [50]. RS-67,333 (XVIII) [51] is a 5-HT4R agonist. Piboserod (XIX)
[52] is a 5-HT4R antagonist.
1.5.5 5-HT5 receptors:
The 5-HT5R has been referred to as one of the “orphan” serotonin
receptors because so little is known about them. DE19900637A1 (XX)
[53] is a 5-HT5R agonist. SB-699,551 (XXI) [54] is a 5-HT5AR antagonist.
1.5.6 5-HT6 receptor:
The 5-HT6R is expressed almost exclusively in the brain [55]. 5-HT6R
plays a major role in functions like emotionality, motor control, memory
and cognition [56, 57]. Blockade of central 5-HT6R has been shown to
increase cholinergic and glutamatergic neurotransmission in various
brain areas [58-61], whereas activation enhances GABAergic signaling in
a widespread manner [62]. Antagonism of 5-HT6R also facilitates
norepinephrine and dopamine release in the frontal cortex, [63] while
stimulation has the opposite effect [62]. Despite the 5-HT6R having a
functionally excitatory action, it is largely co-localized with GABAergic
neurons and therefore produces an overall inhibition of brain activity
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[62]. In parallel with this, 5-HT6R antagonists improve learning, memory
and cognition [64] and agents such as Lu AE58054 (XXII) [65] and SB-
742,457 (XXIII) [66] are being developed as novel treatments for
Alzheimer's disease (AD) and other dementias [67]. 5-HT6R antagonists
have also been shown to reduce appetite and produce weight loss and as
a result, PRX-07034 (XXIV) [68] and BVT-74,316 (XXV) [69] are being
investigated for the treatment of obesity [70]. Recently, the 5-HT6R
agonists WAY-181,187 (XXVI) [71] and WAY-208,466 (XXVII) [71] have
been demonstrated to be active in rodent models of anxiety, depression
and obsessive-compulsive disorder (OCD) and such agents may be useful
treatments for these conditions. The 5-HT6R agonists are EMD-386088
(XXVIII) [72], WAY-181,187 (XXVI) and WAY-208,466 (XXVII). The 5-
HT6R antagonists are MS-245 (XXIX) from Merck [73], compounds XXX,
XXXII to XXXIV [74, 76 - 78] from Suven life sciences and compound
XXXI [75] from Wyeth. The topic will be dealt in further detail in the
following pages.
1.5.7 5-HT7 receptor:
The 5-HT7R is positively coupled to adenylyl cyclase via Gs proteins
[79]. AS-19 drug (XXXV) [80] is a 5HT7R agonist. Amisulpride (XXXVI)
[81] is a 5-HT7R antagonist.
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Table: 1.1 5-Hydroxy tryptamine receptors derivatives.
Receptors Agonist Antagonist
5-HT1A
OH
N
CH3
CH3
I
O
N
NN
N
O
H3C
II
5-HT1B
N
NH
OH3C
NH
III
N
NH
O
N
ON
CH3
CH3
IV
5-HT1D NH
NHCH3H2N
O
V
OH
N
N Cl
VI
5-HT1E NH
O2S
N
CH3
H
VII S
N
N
H3C
SH3C
VIII
5-HT1F NH
HN
O
NCH3
F
IX
VIII
14
5-HT2A
NH
HN
CH3O
N CH3
CH3
X
S
N
N CH3
ON
F
F
XI
5-HT2B NH
NH2
CH3
O
S
XII
N
N
H3C CH3
F
NH2
XIII
5-HT2C
N
F
Cl
NH2
CH3
XIV
N
O NH
N
O
N
H3C
Cl
H3C
XV
5-HT3
HN
HN
NH
NH2
NH
Cl
XVI
NHH3CN
ONN
CH3
XVII
5-HT4
OH3C
H2N
Cl
O
N CH3
XVIII
O
N
O
HN
N
CH3
XIX
15
5-HT5
N
SN
NN
NO
CH3
XX
HN
NN
CH3
CH3
O
XXI
5-HT6
N
NH2
O2S
N
NS
Cl
XXVI
NNH
O
O
N
N
S N
CH3
CH3
Cl
Cl
XXVII
NH
Cl
CH3
NH
XXVIII
NH
HN
O
F
FF
F
F
XXII
N
SO2
N
HN
XXIII
N
NH
O2S
CH3
HN
CH3
O
O
Cl
H3C
H3C
XXIV
O
O2S
NH
CH3
O
O
HN
CH3
XXV
16
N
O2S
N CH3
H3C
OH3C
XXIX
N
O2S
OH3C
N CH3
XXX
N
O2S
F
NCH3
XXXI
N
O2S
Br N
NCH3
F
XXXII
17
N
O2S
NN CH3
XXXIII
N
O2S
NN
CH3
XXXIV
5-HT7
N
N
N
CH3
CH3
CH3
H3C
H3C
XXXV
O2S
H2N
O
NH
N
O
CH3
H3C
CH3
XXXVI
1.6 5-HT6 receptor (5-HT6R) antagonists in clinical development and
cognitive impairment:
The 5-HT6R has received considerable attention due to the interaction
of both atypical and typical antipsychotic drugs, including clozapine
(XXXVII), loxapine (XXXVIII), mianserin (XXXIX) and tricyclic
antidepressants, with this receptor at clinically relevant concentrations
[82 - 88]. The high affinity of atypical antipsychotic for the 5-HT6R and
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its localization in limbic, cortical and striatal regions has driven interest
in the development of more selective 5-HT6R ligands. Antisense
oligonucleotides have been used to better understand the physiological
role of the 5-HT6R [89, 90]. Rats receiving 5-HT6R antisense
oligonucleotides exhibited enhanced performance in the Morris water
maze task [91, 92] providing the first indirect evidence for the
involvement of this receptor in cognition. Ro 04-6790 (XL) and Ro 63-
0563 (XLI) were the first potent and selective 5-HT6R ligands that helped
increase knowledge of the central role of these receptors in-vivo [93].
Structurally diverse molecules such as SB-271046 (XLII) [94, 95] quickly
followed. Although these compounds have been useful tools, they are less
than ideal for in-vivo studies, due mainly to their low brain penetration
after systemic delivery. Persistent drug discovery efforts led to the
discovery of potent compounds with improved brain penetration
including SB-399885 (XLIII), Ro 4368554 (XLIV) and SB-742457 (XXIII)
[96-98]. SB-742457 (XXIII) is the first example of a 5-HT6R antagonist
reported to show efficacy in AD patients [98]. The effect of 5-HT6R
antagonists on social memory is of particular relevance for the treatment
of schizophrenia, in which there are marked deficits in social cognition
[99, 100].The 5-HT6R antagonists SB-271046 (XLII), Ro 4368554 (XLIV)
[97,] SB-258585 (XLV) and SYN-114 (XLVI)[101] reversed scopolamine-
induced amnesia without altering normal social recognition [102]. More
recently the selective 5-HT6R agonist WAY - 181187 (XXVI) was shown to
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impair social recognition in rats [101], an effect that synergized with
scopolamine, suggesting that tonic activation of the 5-HT6R could further
disrupt cognitive processes impacted by a reduction in cholinergic tone.
SB-399885 (XLIII) improved social recognition in normal rats [103].
Microdialysis studies with selective 5-HT6R antagonists have described
the neurochemical effects of these compounds. In addition, 5-HT6R
antagonists induce the release of the excitatory amino acids glutamate
and aspartate neurotransmitters known to play an important role in
learning, long term potentiation (LTP) and memory [104, 105]. Other
neurotransmitters implicated in cognitive function, including
norepinephrine and dopamine [106], are increased by administration of
5-HT6R antagonists. Finally, the release of the inhibitory transmitter
GABA has been found to increase in response to the administration of a
5-HT6R agonist [107]. This suggests that the blockade of 5-HT6R will
reduce the GABAergic inhibition of downstream neurons resulting in
enhancement of excitatory neurotransmission. Additionally 5-HT6R
ligands could have utility as antiobesity agents. A number of preclinical
studies indicated the effects of various 5-HT6R antagonists on food intake
and body weight gain. These studies were followed by evaluation of
several lead compounds in development for obesity [108].
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Table: 1.2 5-HT6R antagonist in clinical development.
NH
NClN
NCH3
XXXVII
O
NN
NCH3
Cl
XXXVIII
N
NCH3
Cl
XXXIX
SO2
HN
N
NHN
HNCH3
CH3
H2N
XL
SO2
HN
N
NH2
HNCH3
H2N
XLI
S
Cl CH3
SO2
HN
O
N
NH
CH3
XLII
Cl
Cl
O
NH
O2S
O
N
NH
CH3CH3
XLIII
NH
N
O2S
N
CH3
XLIV
I
SO2
HN N
OCH3
NCH3
XLV
O
NCl
N
NH
O
F
CF3
XLVI
Most importantly, the structure-activity relationship studies (SAR)
reported by Glennon and coworkers elucidated very important
pharmacophoric elements like the sulfonamide group in the indole series
and revealed pharmacophore requirements for efficient binding to the 5-
HT6R.
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1.7 Indole series:
The first generation of indoles such as 5-methoxy tryptamine (XLVII)
[109, 110] is similarity to 5-HT (XLVIII) and some contained a sulfonyl
moiety linked to the N1 - indole, e.g. MS-245 (XXIX)[111, 112] and WAY-
181187 (XXVI)[113 - 115]. Attached with an aryl-SO2- group at the N1
indole position enhanced potency, while in many cases, converting ligand
function from an agonist to an antagonist [116]. WAY- 181187 (XXVI) is
a good example of a potent and selective 5-HT6R agonist bearing an
imidazothiazolesulfonyl moiety at the N1-indole position. WAY-181187
(XXVI) is presently in clinical development for anxiety [117]. Extensive
SAR studies showed that most potent antagonists like XLIX [117,
118,119], L [83], LI [120], piperazine (e.g. LII), LIII [121], LIV [97], LV
[122], LVI [123], LVII [124] could be obtained by attaching the aryl-
sulfonyl and alkyl amino moieties at different positions on the indole core
than the ones initially found for MS-245 (XXIX). The basic ethylamino
moiety located in MS-245 (XXIX) was successfully replaced by more
constrained moiety such as piperidine (e.g. L), piperazine (e.g. LII), or
alkylpyrrolidine (e.g. LVI). The aryl-sulfonyl moiety can be linked on N1
LI, C5 XLIX, C3 XLIV, or C2 LVof the indole core when the basic
alkylamino moiety is positioned appropriately. This SAR demonstrated
that the spatial orentiation of the alkylamino moiety relative to the aryl
sulfonyl is critical to get potent 5-HT6R ligands. Also the phenyl-sulfonyl
group can be replaced by a sulfonamide LVI, LVII [125] or a
22
sulfonylester moiety as in SGS-518/ LY483518 (LVIII) [126, 127] without
loss of activity. Sulfonamide LVI was a full antagonist, while other
derivatives within the same series (e.g. LVII) were potent partial agonists
[125]. This difference in functional activity between close structural
analogs is confounding and not yet explained. The sulfonylester SGS-
518/LY483518 (LVIII) is a selective 5-HT6R antagonist presently in
phase II clinical trials by Lundbeck for the treatment of cognitive
impairment associated with schizophrenia (CIAS). Previously, in a small
phase II trial, SGS-518/ LY483518 (LVIII) produced a dose proportional
improvement in cognition as determined by the Brief Assessment in
Cognition in Schizophrenia Scale (BACS) [98].
Table: 1.3 5-HT6R reported indoles derivatives
NH
OH3C
NH2
XLVII
NH
HO
XLVIII
N
O2S NH2
CH3
XLIX
N
F
N
O2S
CH3
L
N
O2S
O
NH3C
CH3
LI
N
O2S
N
HN
LII
23
N
N
HN O2S
CH3H3C
LIII
NH
SO2 Cl
ClN
NH
LIV
NH
N
HN
SO2
LV
NH
HN N
SO2
LVI
NH
HN N
SO2
S
CH3
Cl
LVII
N
O
N
CH3
CH3
SO2
F
F
LVIII
1.8 Design and Syntheses:
A general survey of the literature reveals that the reported 5-HT6R
ligands have some major common features that are apparent as the basic
Fig: 1.4
24
minimum pharmacophore, the basic nitrogen, which could be the
primary binding site at the receptor aspartate residue, and two other
aromatic sites, which may be involved in the secondary binding (π-
staking) interactions with the receptor. In an effort to identify and map
the pharmacophoric requirements for the 5-HT6R ligands, several diverse
classes of compounds were taken up for synthesis and evaluation by
various research groups world over. The reported pharmacophoric model
for 5-HT6R ligands was shown in Fig. 1.4 [128], which gives an idea of on
the design of scaffolds that can yield potent ligands at the targeted
receptors.
N1-aryl sulfonyl tryptamine was one of the major classes of
compounds reported as 5-HT6R ligands. Interestingly, although a lot of
work has already been published on the effect of changes made in the
nature of the side chain of tryptamine, the alkyl piperazinyl or other
cyclic amino side chains were not much studied and evaluated on the
indole nucleus. Hence, we initiated research in this direction and the
result was the subject matter of Chapter - 2 to Chapter - 4, leading to N1-
aryl sulfonyl-5-(N-substituted piperzinyl) indole series. A brief account of
the design leading to the conceptualization of this series has been
described in the following pages (Fig. 1.5). Replaced the indolyl moiety
with fused thieno pyrimidine moiety and keeping methylpiperazine
moiety as such and obtained fused thieno pyrimidine derivatives (Fig.
25
1.6). These derivatives were tested in in-vitro analysis and they showed
moderate activity towards 5-HT6R receptor (% inhibition = 40 - 50).
MS-245 (XXIX) is a tryptamine derivative used as a research tool. It
acts as a selective 5-HT6R antagonist with a Ki of 2.3 nM. It has been
used as a lead compound for further development of tryptamine-derived
5-HT6R antagonists. Rigidization of the side chain of MS-245 (XXIX) into
pyrrolidine at the 3-position of indole resulted in a chiral compound
(XXX) that has good antagonist activity (Ki of 0.1nM) towards 5-HT6R.
Pyrrolidine ring expansion into a piperidine ring removed the chirality
while still retaining the potency (XXXI, Ki = 20 nM). Insertion of a second
nitrogen atom into the piperidine ring resulted in a series of potent
molecules (eg XXXII, Ki = 9.2 nM) wherein the piperazine group is
directly liked to the third position of indole nucleus. Insertion of
methylene spacer in the compound (XXXII) resulted in a series of potent
piperazinyl methyl indolyl sulfonamide compounds (eg XXXIII, Ki <20
nM). The CH2 piperazinyl moiety in N1-arylsulfonyl indole-3-
piperzinylmethyl series (XXXIII) was moved from the C3 of indole to the
C4 of indole (XXXIV, Ki <20 nM). In continuation of this studies around
structure XXXIV, we moved –CH2 piperazine moiety to C5 position of
indole, the details of which are given in Chapter 2.
26
DESIGN OF NOVEL N1- SUBSTITUTED BENZENESULFONYL-5-[(N-
SUBSTITUTED PIPERAZIN-1-YL) METHYL]-1H-INDOLES
N
O2S
N CH3
H3C
O
N
O2S
O
N CH3
N
O2S
F
N
N
O2S
Br N
NCH3
N
O2S
N
O2S
NN
R
MS-245.Ki = 2.2nM
SUVENKi = 0.1 nM
WYETH Ki = 20 nM
SUVENKi = 9.2 nM
F
SUVENKi = < 20 nM
Designed Compounds
R2
R1
Ki = 2.5 - 30 nM
Rigidization of side chain
Ring Expantion
CH3
Insertion hetroatom
Insertion of spacer
C3 to C4 Migration
N N CH3
Removal of chirality
structure diversification
(XXIX)
(XXX)
(XXXI) (XXXII)
(XXXIII)
N
O2S
NN
CH3
C4 to C5 Migration
(XXXIV)
SUVENKi = < 20 nM
Fig: 1.5
DESIGN OF NOVEL FUSED THIENO PYRIMIDINES
S N
NR1
R2 N
S
NR3
R4
N
N
Nscaffold hopping
Designed compoundsXXXIII
O2S
Fig: 1.6
To further explore the structure-activity relationship (SAR) scope, the
CH2 piperazinyl moiety in N1-aryl sulfonyl indole-3-piperzinylmethyl
27
series (XXXIII) was moved from the C3 of indole to the C5 of indole. The
SAR exploration of N1-aryl sulfonyl-5-(N-substituted piparazinylmethyl)
indole derivatives lead to the finding that moving the N-methyl
piperazinyl moiety from C3 to C5 of indole maintains the in vitro affinity
(Ki = 2.56 nM - 20.5 nM) of these novel compounds. These compounds
have excellent selectivity over other tested receptors and are active in
NORT and Morris water maze, indicating the cognitive potential of the
compounds. Thus, the compounds from this series are potent, safe,
brain penetrant, highly selective and orally bioavailable 5-HT6R
antagonists having good cognitive potential.
Present Work:
It is evident from the literature described above that 5-HT6R area is
an ideal target to get novel drugs for Alzheimer's disease (AD). So, we
considered it worthwhile to study this target. Accordingly, we have
designed and synthesized a few novel series of molecules and subjected
them to in-vitro and in-vivo evaluation targeting 5-HT6R.
Chapter - 2: This chapter deals with the synthesis of 5-(N-substituted
piperazinyl)-N1-arylsulfonyl-1H-indole derivatives using Leimgruber
method of indole synthesis which involves the condensation of
substituted ortho nitro toluenes with N,N-dimethylformamide dimethyl
acetal followed by reductive cyclization of the resulting trans-β-
dimethylamino-2-nitrostyrene derivatives.
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Chapter - 3: This chapter deals with the synthesis of 5-(N-substituted
piperazinylmethyl)-N1-arylsulfonyl-1H-indoles using reductive amination
of indole-5-carboxaldehyde derivatives with N-substituted piperazines in
presence of sodium triacetoxy borohydride.
Chapter - 4: This chapter deals with the synthesis of 3-chloro-5-(N-
substituted piperazinylmethyl)-N1-arylsulfonyl-1H-indoles using N-
chlorosuccinimide as a chlorinating reagent.
Chapter - 5: This chapter deals with the synthesis of 5-(N-substituted
piperazinylmethyl)-N1-arylcarbonyl and 5-(N-substituted pipe
razinylmethyl)-N1-arylmethyl-1H-indoles using reductive amination
method followed by acylation or aralkylation of indole nitrogen.
Chapter - 6: This chapter deals with the synthesis of fused thieno
pyrimidines using Gewald’s reaction, involving the condensation of a
ketone (or aldehyde) with α-cyanoester in the presence of elemental
sulfur and a base to obtain substituted 2-aminothiophene derivatives.
The latter compounds were converted into fused thieno pyrimidine
derivatives subsequently.
Chapter - 7: This chapter deals with the in-vitro results and the
structure activity relationships of novel 5-(N-substituted piperazinyl)-N1-
arylsubstituted indole derivatives and fused thienopyrimidine derivatives,
whose synthesis was discussed in Chapter - 2 to Chapter - 6, as 5-HT6
receptor ligands.
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