1

Serotonin receptors and its

agonists and antagonists

By

Mohie-Aldien Elsayed Sherief

Assistant professor of pharmacology,

Faculty of medicine , Benha University

2

Contents

-Introduction 1

-Serotonin synthesis 2 -Functions of serotonin 3

-Serotonin receptors 6

-Selective serotonin reuptake inhibitors 15 -Schizophrenia 16

-Migrain 18

-Irritable bowl syndrome 20

3

List of figures: Fig.1) Serotonin balance and its clinical sequelea.------------------- ------------------ 1

Fig.2) Synthesis and metabolism of serotonin.------------------------------------------ 2

Fig 3) The serotonergic synapse. ---------------------------------------------------- 3

Fig 4) serotonin in central nervous system. ------------------------------------------- 4

Fig 5) Effects of serotonin in cardiovascular system . ------------------------------- 5

Fig 6) Serotonin synthesis, receptors and their signal pathway.--------------------- 6

Fig.7) 5-HT receptors location and its signal transduction mechanisms. ---------- 7

Fig.8) 5-HT1A and 5-HT1D autoreceptor . --------------------------------------------- 8 Fig.9) Hypothesized mechanism of serotonin transport across the plasma membrane. ------------------------------

-------------------------------------------- 15

Fig.10) Serotonin reuptake inhibitors with its relative selectivity and other mechanism of

action. --------------------------------------------------------------- 16

Fig.11) Comparative receptor binding profile of atypical antipsychotic. -------- 17

Fig 12) Location of headache.. -------------------------------------------------------- 18

Fig 13) Phases of migraine and therapeutic strategy. ------------------------------- 19

Fig.14) Proposed mechanism of terminating migraine with 5HT 1B,1D --------- 19

Fig.15) Localization of potential relevant molecular targets in irritable bowel syndrome

with the specific. --------------------------------------------------------- 20

Fig.16) Chemical structures of someanorectic drugs and 5HT 2C agonist 22

List of tables: Table 1) Role of serotonin in gastrointestinal function. -------------------------- 7

Table 2) 5HT1 receptors subfamilies, sites, functions and its agonists and antagonists and

its clinical uses ligands. ----------------------------------------- 9

Table 3) 5HT2 receptors subfamilies, sites, functions and its agonists and antagonists and

its clinical uses ligands . ----------------------------------------- 12

Table 4) 5HT3,4,5,6,7 receptors subfamilies, sites, functions and Its agonists and antagonists

and its clinical uses ligands. ------------------------------------------ 14

Table 5) Positive and negative symptoms of schizophrenia. -------------------- 16

Table 6) Typical and Atypical antipsychotic. ------------------------------------ 17

Table 7) Types of headache. --------------------------------------------------------- 18

4

Introduction The greatest concentration, 90%, of Serotonin (5-HT, 5-hydroxytryptamine) is found in

the enterochromaffin cells of the gastrointestinal tract. Most of the remainder of the body's

5HT is found in platelets and the central nervous system (Johnson, 2004). Rapport et al.

discovered serotonin in 1948 as a potent vasotonic factor. For many years, the

physiological effects of 5-HT, including its effects on the CNS, were attributed to only two

major subtypes of 5-HT receptors (Gaddum & Picarelli, 1957).

5-HT is important for a variety of physiological functions, including platelet

aggregation, smooth muscle contraction, appetite, cognition, perception, mood, and other

CNS functions. These diverse physiological functions are mediated by large number of 5-

HT receptor subtypes that are encoded by distinct genes. It now appears that there are at

least 15 receptor subtypes that belong to four classes of receptors: 5-HT1/5, 5-HT2 (A, B, C), 5-

HT3, and 5-HT4/6/7 .5-HT has been implicated in the etiology of numerous diseases states

including depression, anxiety, social phobia, schizophrenia, obcessive-complusive neurosis

and panic disorder; in addition to migraine, hypertension, pulmonary hypertension, eating

disorders, vomiting, and irritable bowel syndrome (Hoyer et al., 1994, Johnson,2004 and

Nagatomo et al,2004),

Fig. 1) Serotonin balance and its clinical sequelea

5

Serotonin synthesis The biosynthesis of serotonin from the amino acid tryptophan is similar to that found

for the catecholamines, and 5-hydroxytryptophan can cross the BBB to increase central

levels of 5-HT. p-Chlorophenylalanine can competitively inhibit tryptophan hydroxylase to

prevent serotonin synthesis. Although serotonin is metabolized by monoamine oxidase to

5-hydroxyindoleacetic acids, most of the serotonin released into the post-synaptic space is

removed by the neuron through a reuptake mechanism inhibited by the tricyclic

antidepressants Serotonin also serves as a precursor for melatonin production in the pineal

gland (Barnes et al, 1999)

Fig. 2) Synthesis and metabolism of serotonin

6

Fig 3) The serotonergic synapse. Illustration of the processes of serotonin synthesis

and metabolism, presynaptic and vesicular 5-HT uptake, vesicular 5-HT release. And

Pre- and postsynaptic 5-HT receptors and sites of action of some serotonergic drugs Functions of Serotonin 1) Sertonin in central nervous system (Only 1-2% serotonin in body)

-involved in sleep induction

-involved in vascular tone: agonists is used in cluster headache and migraine

-Involved in mood: the basis of using selective serotonin uptake inhibitors

- facilitates firing of motorneurons

- involved in ability to differentiate sensory phenomena; reduction of its effect e.g. with the

antagonist LSD, contributes to hallucinogenesis

- involved in temperature regulation in the hypothalamus

- free nerve endings: pain, possible role in acute inflammation (Siegel,1999 ,Nelson ,2004).

Fig 4 shows the serotonin pathways, receptor sites and subtypes and the functions of

serotonin in different parets of the central nervous system

7

Fig 4) serotonin in central nervous system

2-Serotonin in smooth muscle

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on

intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which

are related to the expression of multiple 5-HT receptor types and subtypes regulating

motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT

receptors have gained access to the market for the two major variants of the irritable bowel

syndrome (IBS), a functional disorder characterized by abdominal pain associated with

diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3

receptor antagonist alosetron is available in the US market for the treatment of women with

severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas

tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other

regulatory agencies for the treatment of women with constipation-predominant IBS (C-

IBS) or functional constipation. This review is mainly intended to discuss the role of non-

neuronal (paracrine) and neuronal 5-HT in the pathophysiology of functional

,vomiting centre

Spinal

cord

5-HT 1A,B,E,F , 5-HT 2A,C 5-HT 3,4,5,6

Mood

5-HT1B , 5-HT2A

Amygdala, hipocampus, sleep centers

5 -HT1A, 5-HT2,,5-HT 5,6,7

Anxiety, insomnia

5HT2,6,7

Apetite,bulemia 5-HT 3,7

5HT 3,

sexual dysfunction

5-HT 1A,D

Blood vessel tone,

inflammation

8

gastrointestinal disorders (FGIDs), such as IBS and functional dyspepsia, and the

mechanisms through which drugs acting on 5-HT receptors regulate visceral motility,

perception and secretion in these two conditions. (Tonini and Pace, 2006)

Table 1) Role of serotonin in gastrointestinal function (Tonini

and Pace, 2006)

3) Serotonin in cardiovascular system:

Fig 5) Effects of serotonin in cardiovascular system

Serotonin is an important neurohormonal factor that has been implicated in

cardiovascular function. It can regulate vascular tone, act directly on cardiomyocytes and

stimulate chemosensitive nerves in the heart. The overall effect on blood vessels is

dependent on vessel size, distribution of receptors, and modulation of noradrenergic

VC:5HT7, 5HT2A

VD:5HT1B,D 5HT2A

9

output. The onductance vessels tend to constrict. The transfer vessels: arterioles dilate,

venules constrict and capillaries become more permeable; this favours the formation of

oedema in the inflammatory response. Cardiovascular dysfunction is observed when

serotonin signaling is altered or when variation in serotonin concentration occurs. Recent

studies have provided evidence that, in the absence of peripheral serotonin synthesis, blood

serotonin (which is almost exclusively stored in platelets) is markedly reduced, and that

this drop leads to heart failure. This implies that the level of circulating serotonin is a key

factor in maintaining normal cardiovascular activity. These findings offer new prospects

for the use of serotonin in therapies for cardiovascular diseases. (Cote et al, 2004)

Serotonin receptors

Serotonin receptors are diverse and numerous. More than 15 different serotonin

receptors have been cloned through molecular biological techniques. Overall, seven

distinct families of 5-HT receptors have been identified. Only one of the 5-HT receptors is

a ligand-gated ion channel; the other six belong to the G protein-coupled receptor family

.The amino acid sequences of the 5-HT receptor families are remarkably similar to each

other and to the adrenergic receptor, including a conserved aspartate residue in the third

membrane-spanning segment. Serotonin receptors were divided into several subclasses

based on functional similarities. The 5-HT1 receptors are coupled to the inhibition of

adenylyl cyclase through the Gq/o family of G proteins. In contrast, the 5-HT2 receptors

stimulate phosphoinositide metabolism via Gq/11.(Hoyer et al.,1994 and Jhon et al, 2001).

Fig 6) Serotonin synthesis, receptors and their signal pathway

10

The 5-HT3 receptors are 5-HT-gated ion channels. The basic architecture of the G-

protein-coupled 5-HT receptors is similar to that proposed for nearly all of the G-protein-

coupled receptors (GPCRs). These receptors are integral membrane proteins with 7

putative hydrophobic transmembrane domains connected by 3 intracellular loops (termed

i1–i3) and 3 extracellular loops (termed e1–e3). The amino terminus is oriented toward the

extracellular space, whereas the carboxyl terminus is oriented toward the cytoplasm. The

core proteins also possess conserved or common sites for post-translational modifications.

The extracellular domains are typically glycosylated, and possess cysteine residues that

may participate in disulfide bonds that provide structural constraints on the conformation

of the receptors. The intracellular domains possess sites for interacting with G-proteins and

other regulatory proteins, and sites for phosphorylation by diverse serine-threonine kinases.

(Barnes et al, 1999)

Fig.7) 5-HT receptors location and its signal transduction mechanisms

1) The 5-hydroxytryptamine1 receptors: There are 5 members of the 5-HT1-receptor family, termed 5-HT1A, 5-HT1B, 5-HT1D,

5-HT1E, and 5-HT1F. A receptor formerly termed the 5-HT1C receptor is no longer felt to be

11

a member of the 5-HT1 receptor family, having been reclassified as the 5-HT2C receptor

based on similarities to other 5-HT2 receptors in structure and second messenger systems

(Hoyer et al., 1994),. The 5-HT1 receptors couple primarily through Gi/o-proteins to the

inhibition of adenylyl cyclase (AC) and to other signaling pathways and effectors. Family

G-proteins, resulting in accumulation of phosphatidylinositol 4,5-bisphosphate (PIP2) to

IP3 and DAG. Generation of IP3 results in elevation of intracellular Ca2+

levels, whereas

DAG activates the Ca2+

and phospholipid-dependent protein kinase (John et al 2001).

-The 5-hydroxytryptamine1A receptor

In summary, The 5-hydroxytryptamine1A receptor acts through

* both inhibits and activates adenylyl cyclase

* activates and inhibits phosphatidylinositol-specific phospholipase C

* activates protein kinase C

. * activates the extracellular signal-regulated mitogen-activated protein kinase

* stimulates phosphatidylinositol-3′ kinase

* regulates K+ channels (Kroeze et al 2002 , Green,2006));

The 5-HT1A receptor has also been implicated in morphogenesis and cell survival.

Blockade of endogenous 5-HT1A receptors reverses serotoninergic stimulation of tooth

germ development in mouse mandibular explant cultures (Moiseiwitsch et al., 1998 and

(Adayev et al., 1999)

What is the basis for the multiplicity of 5-hydroxytryptamine1A receptor signaling?

In that regard, the 5-HT1A receptor has been identified in both presynaptic and

postsynaptic locations (Radja et al 1992). The signaling properties and pharmacology of

the presynaptic and postsynaptic 5-HT1A receptors vary somewhat (Clarke et al., 1996),

leading to speculation that there might be subtypes of 5-HT1A receptors (Barnes & Sharp,

1999). Langlois et al. (1996) demonstrated that 5-HT1A receptors transfected into polarized

epithelial LLC-PK1 cells were expressed on both basolateral and apical membranes.

Receptors on both surfaces were able to inhibit cAMP accumulation, albeit with different

efficiencies (Langlois et al., 1996). This study demonstrates that the variables that affect

the multiplicity of signaling from single receptor types are not likely to be manifested as

"all or none" effects. Thus, the specific coupling of single types of 5-HT receptors to

signaling pathways is likely to result from the summation of effects specific to the host cell

milieu (Lefebvre, et al 2001,Hall et al. 1999).

The 5-hydroxytryptamine1B receptor

In summary, the 5-hydroxytryptamine1B receptor act through (Kroeze et al 2002, Green,

2006)) : * regulates adenylyl cyclase

*. activates phospholipases e.g PLC, PLD

* stimulates endothelial nitric oxide production

*Other signals of the 5-hydroxytryptamine1B receptor: Several groups have

demonstrated that presynaptic 5-HT1B receptors decrease 5-HT release. Human 5-HT1B

12

receptors stably transfected in C6 glioma cells activate Ca2+

-dependent K+ channels (Le

Jeong et al, 2005,).

Subfamily Effectors Site Actions Agonists (Used in) Antagonists (Used in)

5-HT1A

(Auto R.

Inhibitory)

Gi: ↓ AC,

open K

channel.

Go: Close

Ca

channel

*CNS: cortex,

Hippocam-

pus, thalamus,

amygdale,

raphe)

*Control

sleep,

feeding,

anxiety

and

ACTH

release.

*Azapiron, Buspirone

, Jaspiron , gepirone

Vilazodone, spiperone

(Anxiety , depression)

*pindolol

*Sarizotane

(L-dopa

dyskinesia)

*Spiroxatrine

(Alzheimer) *SLV310 (psychosis)

5-HT1B

Gi (↓AC) *CNS: cortex,

BG, striatum,

Hypothalamus

*Cerebral &

pulmonary

arteries

* Control

motor

activity ,

behavior

* Control

BV tone.

*Ergometrin,

*Donitriptan,

sumatriptan almotriptan

elctriptan, frovatriptan,

naratriptan ,rizatriptan

(migraine,

hypophagia)

-AR-A2, Elzasonan (Depression, anxiety)

5-HT1D (Auto R.,

Inhibitory

Gi (↓AC) Dorsal raphe,

heart,

meningeal

arteries

BV tone&

inflammat

ion

*Sumatriptan,

almotriptan , elctriptan,

frovatriptan, naratriptan

,Rizatriptan (Migraine)

-

5-HT1E Gi (↓AC) Cortex ? _ _

5-HT1F Gi (↓AC) Brain,

mesentery,

Neuro-

genic

,inflamma

tion

LY-334,370

= Partial agonist, =Inverse agonist , BG=Basal ganglia ,AC=Adenyl cyclase

Table 2) 5HT1 receptors subfamilies, sites, functions and its agonists and

antagonists and its clinical uses ligands. (Miyake et al,1995; John et al, 2001; Raymond et al,

2001; De Vry et al, 2004; Hayashi et al,2004; Palvimaki et al 2005; Jeong et al, 2005; Qvigstad et al 2005;

Green , 2006 , Nelson (2004); Nagatomo et al 2004;Ferreira et al,2004;Tonini M and Pace F,2006;Cote F

et al,2004)

Fig.8) 5-HT1A and 5-HT1D autoreceptor

13

The 5-hydroxytryptamine1D receptor

In summary, the 5-hydroxytryptamine1D acts through;

. * inhibits adenylyl cyclase

* regulates ion channels

*inhibits 5-hydroxytryptamine,glutamate release (LeJeong et al,2005 &Green, 2006).

The 5-HT1E receptor

The 5-HT1E receptor originally was identified as a component of [3H]5-HT binding to

human cortical homogenates that was resistant to a cocktail of antagonists of 5-HT1A, 5-

HT1B/D, and 5-HT2 receptors The intronless 5-HT1E receptor gene was subsequently cloned

from human and rat and The human gene encodes a protein of 365 amino acids. This

protein shares 39% homology with the 5-HT1A receptor and 47% identity (64% in the

transmembrane regions) with the 5-HT1B/D receptors. The 5-HT1E receptor gene has been

localized to human chromosome 6q14-q15 (Zgombick et al, 1996)).

There are few details about signaling pathways linked to the 5-HT1E receptor. Low

concentrations of agonist have been shown to inhibit AC in HeLa and BS-C-1 cells

transfected with the 5-HT1E receptor The 5-HT1E receptor can also stimulate AC, as high

concentrations of agonist also promote increases in cAMP in BS-C-1 cells The 5-HT1E

receptor has not yet been demonstrated to stimulate PLC and/or PLA2. In BS-C-1 cells, 5-

HT had no effect on inositol phosphate release, intracellular Ca2+

levels, or AA

mobilization (Adham et al., 1994)

The 5-hydroxytryptamine1F receptor

The 5-HT1F receptor gene encodes a protein of 366 amino acids, with 70% homology

to the 5-HT1E receptor, 60% to the 5-HT1B receptor (60%), and 63% to the 5-HT1D

receptor. 5-HT1F receptor mRNA was detected in human brain, uterus, and mesentery, but

not in kidney, liver, spleen, heart, pancreas, and testes When stably expressed in NIH 3T3

cells, the 5-HT1F receptor negatively couples to AC (Adham et al, 1994).

The 5-HT1F receptor has been shown to couple to PI-PLC in a cell-specific manner. When

transfected into NIH 3T3 cells, no elevation of inositol phosphates or Ca2+

was observed,

whereas in LM (tk-) cells, the receptor stimulated accumulation of inositol phosphates and

induced a rapid increase of Ca2+

. PLC activation was blocked by pertussis toxin,

supporting a role for the Gi/o-protein . The significance of the coupling to PLC is uncertain,

as the transfected cells used in this study expressed high levels of receptors (4.4 pmol/mg

of protein). The 5-HT1F receptor has been demonstrated to decrease capsaicin-induced c-

fos expression in the rat trigeminal nucleus caudalis, although the signaling pathway of this

effect was not defined (Mitsikostas et al. 1999).

2-The 5-hydroxytryptamine2 receptors There are three members of the 5-HT2 receptor family, termed 5-HT2A, 5-HT2B, and

5-HT2C (Hoyer et al., 1994). The 5-HT2A receptor is probably the 5-HT M receptor

14

described by Gaddum and Picarelli (1957). The 5-HT2B receptor was formerly referred to

as the 5-HT2F receptor [or serotonin receptor like (SRL)] (Foguet et al., 1992), and the 5-

HT2C receptor was previously referred to as the 5-HT1C receptor. The 5-HT2 receptors

couple consistently to the PLC- second messenger pathway (Peroutka, 1995). Unlike the

5-HT1 receptors, the 5-HT2 receptor genes have introns. Although the 5-HT2 receptors are

similar in structure, pharmacology, and signaling pathways, there are a few differences in

their signaling properties ( Grotewiel et al.1999).

The 5-hydroxytryptamine2A receptor

In summary, 5-HT2A act through (Kroeze et al 2002,Green,2006, Bhatnagar et al., 2000,

Bhatnagar et al. (2000). Luparini et al 2004). :

* Activates phospholipase C

* Activates other phospholipases

* Activates the extracellular signal-regulated mitogen-activated protein kinase

* Activates the Janus kinase/signal transducers and activators of transcription pathway

* Regulates channels e.g. Ca2+

,Ca2+

-activated small conductance K+ channel

* Causes production of reactive oxygen and nitrogen species

*Regulates transport processes e.g Na+-proton exchange exchanger, Type 1 Na

+-proton

exchanger in renal mesangial cells

The 5-hydroxytryptamine2B and 2C receptors: The 5-Hydroxttryptamine2B receptor:

5-HT2A was first described as the receptor that mediates contraction of the gastric

fundus (Vane, 1959). The receptor was cloned from rat and mouse in 1992 (Foguet et

al,1992) and from human in 1 (Kursar et al., 1994). The human receptor protein is 481

amino acids in length (Kursar et al., 1994), and it has 2 introns similar to the 5-HT2A and

5-HT2C receptors. The human receptor has 45% homology with the 5-HT2A receptor and

42% homology with the 5-HT2C receptor ( Sharp and Hjorb, 1999). The human 5-HT2B

receptor gene is localized to chromosome 2q36.3-2q37.1. mRNA encoding the 5-HT2B

receptor is expressed with greatest abundance in the human liver and kidney. Lower levels

of expression have been detected in the pancreas and spleen (Bonhaus et al., 1995), but

the presence of mRNA for the 5-HT2B receptor in the brain appears to be relatively limited

(Kursar 1994,Duxon et al., 1997).

The 5-hydroxytryptamine2B receptor act through ((Kroeze et al 2002, Green, 2006):

* activates phospholipase C

* can stimulate cyclic AMP accumulation

*. activates the extracellular signal-regulated kinase and cell cycle components

*The causes production of reactive nitrogen species

And 5-hydroxytryptamine2C receptor act through:

- activates phospholipase C

- receptor can modulate cyclic AMP accumulation

-regulates channels e.g K+ and Cl

− channels

15

Subfamily Effectors Site Actions Agonists (Used in) Antagonists (Used in)

5-HT2A Gq:

*↑PLC

→↑IP3

*↑PLA

→AA

*CNS:

Cortex,

BG

*Sooth

muscle,

*Blood

vessels

*Platelets

*Learning,

antiaggresive,

behaviour)

*Contract SM,

*VC/VD (↑NO) &

↑capillary permeability

* Platelet aggregation, ,

*methyl-5-HT,

LSD

*Citalopram

(aggression)

*Methysergide

*respiridone,

Ketanserine,mianserin

(migraine,depression

*Ritanserin

(Schizophrenia)

*Eplivanserin,

pruvanserin (sleep

disorder)

5-HT2B Gq

*↑PLC→

↑IP3

*↑PLA→

AA

*CNS:

Amygdale

*Stomach

*Anxiolytic,

hyperphagia,

* Contraction

(prokinetic)

locaserin RS127445, SB200648

5-HT2C Gq:

*↑PLC→

↑IP3

*↑PLA→

AA

*CNS:

Cortex

*Choroids

plexus

* Anxiety, sleep, Food

intake

*CSF secretion

-MCCP (obesity)

-D-Fenfluramine,

sibutramine,

fluoxetine

- Agomelatine

(Depression, anxiety,

sleep disorders)

-ACP103

(L-dopa

dyskinesia)

-

Eplivanserin,pruvanse

rin (sleep disorder)

Table 3) 5HT2 receptors subfamilies, sites, functions and its agonists and antagonists

and its clinical uses ligands (Miyake et al,1995; John et al, 2001; Raymond et al, 2001;De Vry et

al, 2004; Hayashi et al,2004; Palvimaki et al 2005; Jeong et al, 2005;Qvigstad et al 2005; Green , 2006 ,

Nelson (2004); Nagatomo et al 2004;Ferreira et al,2004;Tonini M and Pace F(2006);Cote F et al,2004)

Also, 5-HT has significant ability to modulate membrane excitability in

subthalamicneurons; modulation is accomplished by decreasing potassium conductance by

activating 5-HT4 and 5-HT2C receptors (Xiang et al 2005). The 5-HT plays a critical role

in the control of vagaloutflow of the heart. Blocking 5-HTA1 receptors attenuate

bradycardia evoked by stimulating baroreceptor and cardiopulmonary afferent but

notarterial chemoreceptor, whereas antagonizing 5-HT7 receptors markedly attenuated all

these reflex bradycardias (Jordan 2005).

3) The 5-hydroxytryptamine 3 Receptors Unlike most of the other 5-HT receptors, where functional assays were slow to be

identified (and, in some cases, have yet to be identified). Due to the pharmacological

similarity between 5-HT3 receptors and 5-HT-M receptors .5-HT3 receptors are unique

among the families of 5-HT receptors, in that they are nonselective Na+/K+ ion channel

receptors. They are found in the periphery and also in the central nervous system,

particularly in the area postrema, entorhinal cortex, frontal cortex, and hippocampus .

Differences in agonist potencies and efficacies, and antagonist potencies, in various

16

functional assays led to early speculation about 5-HT3 receptor heterogeneity or at least

interspecies variation among 5-HT3 receptors. Furthermore, the distribution of 5-HT3

binding sites in human brain was not identical to that in rodent brain, and the results of

radioligand binding studies using postmortem human brain revealed differences from other

species. Support for interspecies differences has come from molecular biological studies.

5-HT3 receptor cDNA was initially isolated from a mouse neuroblastoma cell line; later, a

splice variant was isolated, human 5-HT3 receptors (hippocampus, amygdala) have been

cloned (Miyake et al, 1995)

4. The 5-hydroxytryptamine4 receptor: Three types of 5-HT receptors couple primarily to the activation of AC: the Gs-coupled 5-

HT4, 5-HT6, and 5-HT7 receptors (Hamblin et al., 1998). Unlike the 5-HT6 and 5-HT7

receptors, the 5-HT4 receptor was well-characterized pharmacologically and functionally

prior to its cloning. The major functional effects of the 5-HT4 receptors are prokinetic

actions in the gut and positive inotropy, chronotropy, and lusitropy in atria, but not

ventricles (Kaumann, 1991).

The human 5-HT4 gene is thought to be highly complex, with multiple introns). It maps

to chromosome 5q31-q33 In 1995, Gerald et al. reported the isolation of two rat brain 5-

HT4 receptors. These were originally termed 5-HT4S and 5-HT4L to indicate that they are

short (387 amino acids) and long versions (406 amino acids) of the 5-HT4 receptor

(Bockaert et al., 1998). Similar murine cDNA homologues of these receptors were

subsequently reported , and these were proposed to be renamed 5-HT4a and 5-HT4b

receptors, to be more in keeping with the recommendations of the Nomenclature

Committee of the International Union of Pharmacology ..5-HT4a, 5-HT4b, and 5-HT4c

receptors are expressed in the brain, the atrium, and the gut, whereas the 5-HT4d receptor

has only been detected in the gut The human 5-HT4d receptor is localized in the atrium and

the brain, but not in the gut .Functional ventricular 5-HT(4) receptors are induced by

myocardial infarction and CHF of the rat heart. We propose that they are a model for

ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological

role in heart failure (Kroeze et al 2002 &Qvigstad et al 2005,,Green,2006)

5. The 5-hydroxytryptamine5 receptors Currently, little is known about 5-ht5 receptors. As functional 5-ht5 receptors have not

been identified in vivo yet, the lower case designation is used. Cloning experiments have

revealed two subtypes of the 5-ht5 receptor, termed 5-ht5a and 5-ht5b. Both 5-ht5a and 5-ht5b

receptors have been cloned from rat and mouse, but only the 5-ht5a receptor has been

cloned from human . The human 5-ht5A receptor gene encodes a protein of 357 amino acid

residues, has a single intron, and is located on chromosome 7q36 (Rees et al., 1994).

The 5-HT5 receptors have high affinity for lysergic acid diethylamide (LSD) and 5-

carboxamidotryptamine. Both receptors are expressed in multiple brain regions, but not in

peripheral tissues (Rees et al,1994). Waeber et al (1995) were able to identify putative 5-

17

ht5a receptors by comparative autoradiography with [3H]5-carboxamidotryptamine and

[125

I]LSD in wild-type and 5-ht5a receptor knockout mice. Studies with [3H]5-

carboxamidotryptamine (in the presence of 8-OH-DPAT, GR127935, and spiperone)

revealed no binding in knockout mice, but intermediate levels of binding in wild-type mice

in the olfactory bulb and neocortex. This binding probably represents the 5-ht5a receptor.

(Waeber et al., 1998).

Subfamily Effector Site Actions Agonists

(Used in) Antagonists (Used in)

5-HT3 Open

cation

channel

*CNS: cortex,

NTS, area

postrema

*Peripheral

sensory nerves

(vagus,splanchic)

*Enteric neurone

*Anxiety,

vomiting,

Gut motility

*Pain, itching,

↑transmitter

release.

*Transmitter

release,

Secretion

2-methyl-5-

HT

-Ondansetrone,

Dolasetron, granisetron,

tropisetron (Used in

chemotherapy induced

emesis)

-Alosetrone ,

Cliansetrone, mosapride,

rinzapride (used in IBS

with diarrhea)

5HT4 Gs (↑AC)

*Enteric neurone

* Atria,

*Brain

(stimulatory)

*Transmitter

release, relaxation

& Secretion

(Prokinetic) *↑ HR

*?

*Tegaserod

, Mosapride,

Prucaloprid,

renzapiride

(IBS+ cons-

tipation &

GIT

disorders)

-

5-HT5A ? Gs

(?AC)

Brain Brain

development

_ _

5HT5B ? Gs

(?AC)

Hippocampus _ _

_

5-HT6 Gs (↑AC)

Limbic system,

cortex,

hippocampus

Cognition,

feeding, affected

disorders,

seizures.

EDMT -Gw742457 (psychosis)

– BVTS-5182S

(Obesity)

5-HT7 Gs (↑AC)

BV, SM, brain

stem,

hypothalamus,

hippocampus,

VD, sleep,

temperature

control

5CT, 5-

MeOt

SB258719,SB258741.

-Paliperidone

(psychosis)

Table 4) 5HT 3,4,5,6,7 receptors subfamilies, sites, functions and Its agonists and

antagonists and its clinical uses ligands (Miyake et al, 1995; John et al, 2001; Raymond et al,

2001;De Vry et al, 2004; Hayashi et al, 2004; Palvimaki et al 2005; Jeong et al, 2005;Qvigstad et al 2005;

Green , 2006 , Nelson (2004); Nagatomo et al 2004;Ferreira et al,2004;Tonini M and Pace F(2006);Cote

F et al,2004 )

18

7. The 5-hydroxytryptamine7 receptor

The 5-hydroxytryptamine7 receptor act through (Kroeze et al 2002,Green,2006))

* activates adenylyl cyclase

* activates the extracellular signal-regulated kinase

*. modulates slow afterhyperpolarization

6. The 5-hydroxytryptamine6 receptor

(The human 5-HT6 receptor is a 440 amino acid protein. The gene contains two

introns that correspond to regions of the putative i3 and e3 loops .The gene for the receptor

maps to the human chromosome region 1p35-p36 (Kohen et al., 1996). The 5-HT6 receptor

stimulates AC and has high affinity for typical and atypical antipsychotics, including

clozapine. The receptor is expressed in several brain regions, most prominently in the

caudate nucleus, the olfactory tubercle, the striatum, the hippocampus, and the nucleus

accumbens . Low levels of 5-HT6 receptor mRNA are also expressed in the adrenal gland

and the stomach Surprisingly, 5-HT6 receptors appear to regulate cholinergic (rather than

dopaminergic) neurotransmission in the brain, implicating it as a target for the treatment of

learning and memory disorders (Bourson et al 1998,Wolley et al 2004,Kroeze et al

2002,Green, 2006). Selective Serotonin reuptake inhibitors Serotonin transport across the plasma membrane:

•Serotonin uptake is a carrier-mediated process requiring the presence of Na+ and Cl-

ions. Sodium binds first to the carrier, followed by 5-HT (1).

•Chloride is needed for transport but not for transmitter binding. The carrier is

translocated in the membrane by an unknown mechanism, after which 5-HT and the ions

dissociate from their binding sites (2).

•Potassium then binds to the carrier (3), is translocated to the outside of the membrane

(4), and dissociates from the carrier to complete the cycle.

Fig.9) Hypothesized mechanism of serotonin transport across the plasma membrane

19

Fig. 10) Serotonin reuptake inhibitors with its relative selectivity and other mechanism of action.

Clinical indications of SSRI :

1-Major Depression&2nd to medical condition (e.g Post stroke)

2-Paraphillias, sexual addictions & premature ejaculation.

3-Obesity &Weight gain in smokers &Bulimia nervosa.

4-Emotional liability following brain injury.

5-Migraine prophylaxis. 6-Diabetic neuropathy.

7-Seasonal Affective Disorder. 8-Obsessive-compulsive disorder

9-Panic Disorder& Social phobia 10-Borderline personality disorder.

11-Depersonalization syndrome 12-Alcoholism Schizophrenia

Schizophrenic symptoms can represent either an excess or distortion of normal

function (positive symptoms) or a decrease or loss of normal function (negative symptoms).

Table 5) Positive and negative symptoms of schezophrenia

Positive symptoms Negative symptoms

1- Thought disorders e.g. delusion. 1- Poverty of though and speech.

2- abnormal perception e.g.hallucination. 2- Impaired volition

3-Inappropriate affect (affective response is

Incompatible with the ideas or thoughts expressed)

3- Blunt affect and anhedonia

4- Disorganized behavior. 4- Social withdrawal

20

Antipsychotic (Neuroleptics)

*All have epileptogenic potentials * All available in Oral preparation

Table 6) Typical and Atypical antipsychotic

Fig.11) Comparative receptor binding profile of atypical antipsychotic

Typical Atypical

* High affinity (blocker) to D2. *High 5HT2, D4 & weak D2 (blocker) affinity.

* Decrease negrostriatal &

mesolimbic dopaminergic activity.

* Decrease mainly the mesolimbic dopaminergic

activity.

* More effective in treatment of

positive symptoms

* Affect both negative and positive symptoms.

* More adverse effect :

1-Extrapyrmidal side effect(EPS), the

higher potency, the higher EPS.

2-Sedation (D2,H1 & α1 blockade).

3-Anticholinergic.

4-Postural hypotension.

5-Hyperprolactinaemia & sexual

dysfunction:

e.g. a- Phenothizines.

b- Thioxanthines (flupenthixol).

c-Butyrophenone (flupenthixol).

d- Diphenylbutyl piperidine

* Diabetes + Drug’s specific adverse effect:

e.g :a- Clozapin (fatal agranulocytosis, high

anticholinergic & sedation, weight gain).

b- Resperidon (EPS in dose > 6 mg/day).

c- Sertindol (nasal congestion, sexual

dysfunction).

d- Olanzapine (sedation & weight gain).

e- Quetiapine (postural hypotension).

21

Migraine Migraine is a chronic, neurological disorder generally manifesting itself in attacks

with severe headache, nausea and an increased reactivity to sensory stimuli. The discovery

of the triptans (selective 5-HT1B/1D receptor agonists) gave an alternative therapeutic

approach to the acute treatment of migraine. Sumatriptan, the first to be developed, is the

most extensively studied medication in the history of migraine. Its emergence onto the

market generated intense pharmaceutical research and the development of a number of

second-generation agents, including almotriptan, eletriptan, frovatriptan, naratriptan,

rizatriptan and zolmitriptan. (Linde, 2006)

Type Location Severity Symptoms

Migrains Unilateral Usually

severe

*Prodrome (anxiety, irritability, euphoria or drowzness,

sensitive to sound, light, smell): hours to days before headache

*Aura: 5-20 m before headache,visual (zigzag lines,

paraesthesia &visual defect) is the commenst)

*Headache: Throbbing, nausea Last a long time.

*Postdrome: follow sever attacks (exhaustion and scalp

tenderness)

Cluster Unilateral Usually

severe

Autonomic: affect eye and nose Brief15-90 m)

Tension Diffuse Rarely

severe

Dull, nonthrobbing, no nausea Worsened by stress

Table 7) Types of headache

Fig 12) Location of headache

22

A migraine trigger causes the release of neuropeptide from 5HT-1D receptorsin the

trigeminal vascular junction which in turn induce sterile inflammation of the meningeal

arteries via 5HT-1D receptors. The throbbing of the meningeal arteies is transmitted into

the thalamus and interpreted as pain.abnormal neurologic impulses produce a central effect

with nausea, vomiting,dizzness and light and sound sensitivity.Triptans block 5Ht-1D and

5HT-1B receptors,thus deactivating the mechanisms that propagates migrain (Rapoport et

al 2006)

Irritable bowel syndrome Fig.14) Proposed mechanism of terminating migraine with 5HT 1B,1D

Fig 13) Phases of migraine and therapeutic strategy

23

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel

disorders characterised by a diverse consortium of abdominal symptoms including

abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating,

abdominal distension, the sensation of incomplete evacuation and the increased passage of

mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put

forward to explain symptom production in IBS. The currently favoured model includes

both central and end-organ components which may be combined to create an integrated

hypothesis incorporating psychological factors (stress, distress, affective disorder) with

end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by

sub-clinical inflammation as a residuum of an intestinal infection. There is currently no

universally effective therapy for IBS. Standard therapy generally involves a symptom-

directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for

constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug

development has focused predominantly on agents that modify the effects of 5-

hydroxytryptamine (5-HT) in the gut, principally the 5-HT3 receptor antagonists for painful

diarrhoea predominant IBS and 5-HT4 agonists for constipation predominant IBS. More

speculative new therapeutic approaches include anti-inflammatory agents, antibiotics,

probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors. (Farthing, 2004, Bradesi et al , 2006).

Fig. 15) Localization of potential relevant molecular targets in irritable bowel

syndrome with the specific classes of agents discussed in this Review

24

. 5-HT3 antagonists Alosetron and cilansetron have been evaluated in randomized,

controlled trials and both are considered to have efficacy in female patients with diarrhea-

predominant IBS Indeed, in a first major study, alosetron was shown to have a 12%

therapeutic advantage over placebo, using an end point of adequate relief of IBS pain and

discomfort for at least two weeks per month. Several other Phase III studies have

confirmed these results. Cilansetron was shown to have similar efficacy in a Phase III

study in a similar female IBS population. One of the major problems with the use of both

alosetron and cilansetron is a high prevalence of ischemic colitis, which might be linked to

a direct or indirect action of 5-HT3 antagonists on colonic blood flow. (Bradesi et al,

2006).

Tegaserod a selective 5-HT4 receptor partial agonist, has prokinetic properties by virtue

of stimulating peristalsis and increasing both intestinal and colonic transit, and also by

modulating sensory pathways . Clinical trials in constipated female IBS patients, with end

points comprising a global improvement, and an improvement in bowel frequency, stool

consistency or abdominal pain at three months, indicate a 9.3% higher percentage than

placebo. The limited side effects observed included transient diarrhea and a higher than

expected rate of cholecystectomy (Shoenfeld, 2004)

Renzapride (mixed 5-HT4 agonist and 5-HT3 antagonist) has been evaluated in IBS

treatment. As a 5-HT4 agonist, it might stimulate gastrointestinal and colonic contractions

and transit. Evidence of a potentially favorable outcome in the treatment of IBS with

renzapride is based on Phase IIb trials in constipated IBS or mixed-symptom IBS. A dose-

related acceleration of colonic transit in constipated IBS patients and an improvement in

stool consistency and passage have been demonstrated after two weeks of treatments

(Camilleri et al,2004)

Obesity

Central biogenic amine systems have long been studied for their effects on feeding

behavior, energy balance, and maintenance of body weight. Those monoaminergic systems

that use dopamine, norepinephrine and serotonin as neurotransmitters have been the main

targets of study. A number of antiobesity medications that affect monoaminergic activity

have appeared on the market and/or in clinical trials. Early examples of such agents are the

so-called CNS stimulants, e.g., the amphetamines, phentermine, ephedrine, etc. These

agents release monoamines from neuronal stores, and their antiobesity activity seems to be

tied most closely to their ability to release NE. Inhibitors of neuronal reuptake of NE or 5-

HT have been shown to reduce feeding and weight gain both preclinically and clinically.

However, the magnitude and sustainability of such effects in clinical trials has generally

not been great enough to register or label these agents for the treatment of obesity.

Sibutramine, however, is an exception. This compound is metabolized in vivo to produce

metabolites that have varying degrees of inhibition of NE, 5-HT, and/or DA uptake.

Sibutramine is the only drug affecting monoaminergic systems currently approved for the

25

long-term control of obesity. Research continues on serotonergic and histaminergic

systems to determine if targets such as the 5-HT2C and H3 receptors may be suitable for

developing antiobesity agents. Because the clinical antiobesity effects of monoaminergic

drugs have been modest, future directions include looking at combinations of different

monoaminergic mechanisms and/or combinations of monoaminergic drugs with non-

monoaminergic mechanisms. Nelson and Gehlert ,2006) .

In light of the extensive data supporting the therapeutic potential of 5-HT2C receptor

agonists for the treatment of obesity, numerous reports on the development of 5-HT2C

receptor agonist compounds have appeared in the literature in recent years. Research

efforts at several pharmaceutical companies have resulted in the identification of potent

and subtype-selective 5-HT2C receptor agonists with promising properties as potential

antiobesity agents. (Nilsson,2006)

Fig.16) Chemical structures of someanorectic drugs and 5HT 2C agonist (Smith et al,2006)

26

References 1. Adayev, T., El-Sherif, Y., Barua, M., Penington, N.J. and Banerjee, P.: Agonist

stimulation of the serotonin1A receptor causes suppression of anoxia-induced

apoptosis via mitogen-activated protein kinase in neuronal HN2-5 cells.J

Neurochem. 1999 Apr;72(4):1489-96..

2. Adham N, Vaysse PJ-J, Weinshank RL, Branchek TA. The cloned human 5-HT1E

receptor couples to inhibition and activation of adenylyl cyclase via two distinct

pathways in transfected BS-C-1 cells. Neuropharmacology 1994;33:403-410.

3. Barnes, N.M. and Sharp, T., A review of central 5-HT receptors and their function.

Neuropharmacology 1999,38, 1083–1152.

4. Bhatnagar, A., Willins, D.L., Gray, J.A., Woods, J., Benovic, J.L. and Roth, B.L.,

The dynamin-dependent, arrestin-independent internalization of 5-

hydroxytryptamine 2A (5-HT2A) serotonin receptors reveals differential sorting of

arrestins and 5-HT2A receptors during endocytosis. .. J Biol Chem., 2001 276,

8269–8277.

5. Bockaert, J., Claeysen, S., Sebben, M. and Dumuis, A., 1998. 5-HT4 receptors:

gene, transduction and effects on olfactory memory. Ann N Y Acad Sci 861, pp. 1–

15.

6. Bradesi S,Tillisch K,Mayer E Emerging drugs for irritable bowel syndrome. Expert

Opin Emerg Drugs..2006 May;11(2):293-313

7. Bonhaus, D.W., Bach, C., DeSouza, A., Salazar, F.H., Matsuoka, B.D., Zuppan, P.,

Chan, H.W. and Eglen, R.M.: The pharmacology and distribution of human 5-

hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A

and 5-HT2C receptors. Br J Pharmacol.,1995.. 115, pp. 622–628

8. Bourson, A., Boess, F.G., Bos, M. and Sleight, A.J., Involvement of 5-HT6

receptors in nigro-striatal function in rodents. Br J Pharmacol 1998,125, pp. 1562–

1566.

9. Camilleri M,. McKinzie S,. Fox J, Foxx-Orenstein A.,. Burton D,. Thomforde G,.

Baxter K and. Zinsmeister A.R, Effect of renzapride on transit in constipation-

predominant irritable bowel syndrome, Clin Gastroenterol Hepatol 2 (2004), pp.

895–904

10. Clarke, W.P., Yocca, F.D. and Maayani, S., Lack of 5-hydroxytryptamine1A-

mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats. J

Pharmacol Exp Ther 1996.. 277 ;1259–1266.

11. Cote F;Fligny C;Fromes Y;Mallet J(2004);Recent advancein understanding

serotonin regulationof cardiovascular function.Trends in Molecular

Medicine;10;5;232-238

12. De Vry J, Schreiber R, Melon C, Dalmus M, Jentzsch KR, -HT1A receptors are

differentially involved in the anxiolytic- and antidepressant-like effects of 8-OH-

27

DPAT and fluoxetine in the rat. Eur Neuropsychopharmacol. 2004 Dec ;14(6):487-

95.

13. Duxon, M.S., Flanigan, T.P., Reavley, A.C., Baxter, G.S., Blackburn, T.P. and Fone,

K.C., Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the

rat central nervous system. 1997.. Neuroscience 76, pp. 323–329.

14. Farthing MJ .Treatment options in irritable bowel syndrome.Best Pract Res Clin

Gastroenterol. 2004 Aug;18(4):773-86.

15. Ferreira HS, de Castro e Silva E, Cointeiro C, Oliveira E, Faustino TN, Fregoneze

JB. Role of central 5-HT3 receptors in the control of blood pressure in stressed and

non-stressed rats. Brain Res. 2004 Nov 26; 1028(1):48-58.

16. Foguet, M., Nguyen, H., Le, H. and Lubbert, H., Structure of the mouse 5-HT1C,

5-HT2 and stomach fundus serotonin receptor genes. S Neuroreport.1992. 3, pp.

345–348.

17. Gaddum, J.H. and Picarelli, Z.P., Two kinds of tryptamine receptor. Br J

Pharmacol.1957,12, 323–328.

18. George J. Siegel (1999) “Understanding the neuroanatomical organization of

serotonergic cells in brain provides insight into the functions of this

neurotransmitter”, Basic Neurochemistry, Bernard W. Agranoff, Stephen K. Fisher,

R. Wayne Albers, Michael D. Uhler, Sixth, Lippincott Williams and Wilkins. ISBN

0-397-51820-X. “In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-

Hillarp technique of histofluorescence, observed that the majority of serotonergic

soma are found in cell body groups, which previously had been designated as the

raphe nuclei.”

19. Green AR (2006);Neuropharmacology of 5-

hydroxytryptamine;B.J.Pharmacol.;147;S145-S125

20. Grotewiel, M.S. and Sanders-Bush, E.,. Differences in agonist-independent activity

of 5-HT2A and 5-HT2C receptors revealed by heterologous expression. Naunyn

Schmiedebergs Arch Pharmacol .1999,359, pp. 21–27

21. Hall, R.A., Premont, R.T. and Lefkowitz, R.J., Heptahelical receptor signaling:

beyond the G protein paradigm.. J Cell Biol 1999,145, pp. 927–932.

22. Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J.,

Saxena, P.R. and Humphrey, P.P.,. International Union of Pharmacology

classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev

1994,46, pp. 157–203.

23. Jeong HS, Jang MJ, Park JS. Effects of CGS-12066A on medial vestibular nuclear

neurons.Brain Res. 2005 Mar 15;1038(1):118-21.

24. Johnson BA.. Role of the serotonergic system in the neurobiology of alcoholism:

implications for treatment , CNS Drugs 2004;18(15):1105-18.

28

25. Kroeze W,Kristiansen K,Roth B(2002);Molecular biology of serotonin receptors-

structure and function at molecular level.Current Topics in Medicinial

Chemistary;2;507-528

26. Kursar, J.D., Nelson, D.L., Wainscott, D.B. and Baez, M., Molecular cloning,

functional expression, and mRNA tissue distribution of the human 5-

hydroxytryptamine2B receptor... Mol Pharmacol 1994,46, pp. 227–234.

27. Langlois X, el Mestikawy S, Arpin M, Triller A, Hamon M, Darmon M.Differential

addressing of 5-HT1A and 5-HT1B receptors in transfected LLC-PK1 epithelial

cells: a model of receptor targeting in neurons.. Neuroscience 1996,74, pp. 297–302

28. Lefebvre H, Dhib M, Godin M, Contesse V, Delarue C, Rieu M, Wolf LM, Vaudry

H, Kuhn JM. Effect of the serotonin 5-HT4 receptor agonist cisapride on aldosterone

secretion in corticotropic insufficiency and primary hyperaldosteronism.

Neuroendocrinology ,1997, 66, pp. 229–233.

29. Linde M Migraine: a review and future directions for treatment Acta Neurol

Scand. 2006 Aug;114(2):71-83.

30. Luparini MR, Garrone B, Pazzagli M, Pinza M, Pepeu G. A cortical GABA-5HT

interaction in the mechanism of action of the antidepressant trazodone Prog.

Neuropsychopharmacol Biol Psychiatry. 2004; 28(7): 1117-27.

31. Mitsikostas, D.D., Sanchez del Rio, M., Moskowitz, M.A. and Waeber, C., Both 5-

HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal

nucleus caudalis... Eur J Pharmacol ,1999,369, pp. 271–277.

32. Miyake A, Mochizuki S, Takemoto Y, Akuzawa S:Molecular cloning of human 5-

hydroxytryptamine 3 receptor: heterogeneity in distribution and function among

species.. Mol Pharmacol 1995;48:407-416.

33. Moiseiwitsch J.R., Raymond, J.R., Tamir, H. and Lauder, J.M.: Regulation by

serotonin of tooth-germ morphogenesis and gene expression in mouse mandibular

explant cultures... Arch Oral Biol 1998, 43, pp. 789–800.

34. Monsma, F.J., Shen, Y., Ward, R.P., Hamblin, M.W. and Sibley, D.R., Cloning and

expression of a novel serotonin receptor with high affinity for tricyclic psychotropic

drugs.. Mol Pharmacol 1993,43, pp. 320–327.

35. Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T.: Functions of 5-HT2A

receptor and its antagonists in the cardiovascular system .Pharmacol Ther.

2004,104(1): 59-81

36. Nelson DL (2004)5-HT receptors.Current Drug Target CNS Neurol.

Disord;3(1);53-58

37. Nilsson BM (2006) 5-Hydroxytryptamine 2C (5-HT2C) receptor agonists as

potential antiobesity agents. J Med Chem. 2006 Jul 13;49(14):4023-34.

38. Nelson DL and Gehlert DR (2006) Central nervous system biogenic amine targets

for control of appetite and energy expenditure, Endocrine. ;29(1):49-602006)

29

39. Palvimaki EP, Majasuo H, Syvalahti E, Hietala J. Serotonin 5-HT2C receptor-

mediated phosphor-inositide hydrolysis in rat choroid plexus after fluoxetine and

citalopram treatments. Pharmacol Res. 2005 May;51(5):419-25.,

40. Peroutka, S.J., 1995. 5-HT receptors: past, present and future. Trends Neurosci 18,

pp. 68–69.

41. Radja, F., Daval, G., Hamon, M. and Verge, D.: Pharmacological and

physicochemical properties of pre-versus postsynaptic 5-hydroxytryptamine1A

receptor binding sites in the rat brain: a quantitative autoradiographic study.. J

Neurochem , 1992, 58,1338–1346.

42. Rapport, M.M., Green, A.A. and Page, I.H., 1948. Crystalline serotonin. Science

108, pp. 329–330.

43. Rapoport AM,Tepper SJ,Sheftell FD,Kung E,Bigal ME (2006)Which triptan for

which patient? . Neurol Sci., May;27 Suppl 2:S123-9. 44. Rees, S., den Daas, I., Foord, S., Goodson, S., Bull, D., Kilpatrick, G. and Lee, M.,

(1994) Cloning and characterisation of the human 5-HT5A serotonin receptor...

FEBS Lett,355, pp. 242–246.

45. Qvigstad E, Brattelid T, Sjaastad I, Andressen KW, Appearance of a ventricular 5-

HT4 receptor-mediated inotropic response to serotonin in heart failure. Cardiovasc

Res. 2005 1;65(4):869-78.

46. Saudou, F. and Hen, R., -Hydroxytryptamine receptor subtypes in vertebrates and

invertebrates... Neurochem Int 1994,25, pp. 503–532

47. Sharp, T. and Hjorth, S., Application of brain microdialysis to study the

pharmacology of the 5-HT1A autoreceptor. J Neurosci Methods 1990,34, pp. 83–90.

48. Shoenfeld P., Systematic review: incidence of abdominal/pelvic surgery amongst

patients using tegaserod in randomized controlled trials, Aliment Pharmacol Ther 19

(2004), pp. 263–269

49. Smith BM,Thomson WJ,Grottick AJ (2006) The potential use of selective 5HT 2C

agonist in treating obesity.Expert Opin.Invest.Drugs,15(3),257-266.

50. Tonini M, Pace F (2006): Drugs acting on serotonin receptors for the treatment of

functionalGI disorders;Dig.Dis;24;59-69

51. Vane, J.R., The relative activities of some tryptamine analogues on the isolated rat

stomach strip preparation.. Br J Pharmacol Chemother 1959,14, pp. 87–98.

52. Waeber, C., Grailhe, R., Yu, X.J., Hen, R. and Moskowitz, M.A., Putative 5-ht5

receptors: localization in the mouse CNS and lack of effect in the inhibition of dural

protein extravasation... Ann N Y Acad Sci 1998, 861, pp. 85–90.

53. Wolley ML; Marseden MA; Fon KC.(2004);5HT6 receptors;Current Drug

Targets.CNS and neurological disorders;3;59-69

54. Xiang Z, Wang L, Kitai ST. Modulation of spontaneous firing in rat subthalamic

neurons by 5-HT receptor subtypes J Neurophysiol. 2005 Mar;93(3):1145-57

30

55. Zgombick JM, Schechter LE, Adham N, Kucharewicz SA, Weinshank RL,

Branchek TA.Pharmacological characterizations of recombinant human 5-HT1D

alpha and 5-HT1D beta receptor subtypes coupled to adenylate cyclase inhibition in

clonal cell lines: apparent differences in drug intrinsic efficacies between human 5-

HT1D subtypes., 1996.. Naunyn Schmiedebergs Arch Pharmacol 354, 226–236.