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

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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-

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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.


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.


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)



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.


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.


The 5-HT7R is positively coupled to adenylyl cyclase via Gs proteins

[79]. AS-19 drug (XXXV) [80] is a 5HT7R agonist. Amisulpride (XXXVI)


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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

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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

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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.

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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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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.


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.

chapter - 1 introduction to g-protein coupled receptors...

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