Post on 28-Jan-2016
CMOA 1CMOA 15
5-HT4 Receptor Physiology and Pharmacodynamic Effects of
Tegaserod
5-HT4 Receptor Physiology and Pharmacodynamic Effects of
Tegaserod
Michael Camilleri, MD
Gastroenterology Research UnitMayo Clinic Foundation
Michael Camilleri, MD
Gastroenterology Research UnitMayo Clinic Foundation
CMOA 2CMOA 25
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist,
and its pharmacodynamic effects on the GI tract
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist,
and its pharmacodynamic effects on the GI tract
CMOA 3CMOA 3
Physiologic Distribution of Serotonin(5-Hydroxytryptamine, 5-HT)
Physiologic Distribution of Serotonin(5-Hydroxytryptamine, 5-HT)
5% CNS5% CNS
95% GI tract
90% EC s 10% Neurons
95% GI tract
90% EC s 10% Neurons
5-Hydroxytryptamine5-Hydroxytryptamine
NH2
OH
NH
5
CMOA 4CMOA 45
Role of 5-HT in the GI TractRole of 5-HT in the GI Tract
Four main 5-HT receptor subtypes identified in the human GI tract : 5-HT1, 5-HT2, 5-HT3, and 5-HT4
– Diverse effects due to different receptor subtypes
5-HT3 and 5-HT4 receptors involved in multiple GI functions: motor, sensory, secretory
Location of 5-HT4 receptors: neurons, EC cells, enterocytes, smooth muscle cells
Four main 5-HT receptor subtypes identified in the human GI tract : 5-HT1, 5-HT2, 5-HT3, and 5-HT4
– Diverse effects due to different receptor subtypes
5-HT3 and 5-HT4 receptors involved in multiple GI functions: motor, sensory, secretory
Location of 5-HT4 receptors: neurons, EC cells, enterocytes, smooth muscle cells
Inhibition
5
SerosaLongitudinal muscleSerosaLongitudinal muscle
Myenteric plexusMyenteric plexus
Submucosal plexusSubmucosal plexus
Muscularis mucosaeLamina propriaEpithelium
Muscularis mucosaeLamina propriaEpithelium
Circular muscleCircular muscle
Dorsal Root Ganglion
Intrinsic Signaling PathwaysIntrinsic Signaling PathwaysMOA 5MOA 5
Intrinsic primaryafferent neuronsIntrinsic primaryafferent neurons
EnterocytesEnterocytes ECsECs
Extrinsic primaryafferent neurons
ECs
CNS
Inhibitorymotor neuron
Excitatorymotor neuron
5-HT
ActivationActivation
ECs: Enterochromaffin cellsECs: Enterochromaffin cells
5-HT4 receptor
5
Intrinsic primaryafferent neurons
SerosaLongitudinal muscleSerosaLongitudinal muscle
Myenteric plexusMyenteric plexus
Submucosal plexusSubmucosal plexus
Muscularis mucosaeLamina propriaEpithelium
Muscularis mucosaeLamina propriaEpithelium
Circular muscleCircular muscle
EnterocytesEnterocytes ECsECs
Inhibitorymotor neuron
Excitatorymotor neuron
Extrinsic Signaling PathwaysExtrinsic Signaling PathwaysMOA 6MOA 6
Extrinsic primaryafferent neuronsExtrinsic primaryafferent neurons
ECsECs
Dorsal Root GanglionDorsal Root Ganglion
CNSCNSInhibitionInhibition
ECs: Enterochromaffin cellsECs: Enterochromaffin cells
5-HT4 receptor
CMOA 7CMOA 75
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects
– Effects on motility– Effects on visceral sensitivity
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects
– Effects on motility– Effects on visceral sensitivity
CMOA 8CMOA 8
SerotoninSerotonin
5
NH2
OH
NH
N
O
NH
NH
NHNH
TegaserodTegaserod
TegaserodTegaserod
A representative of a new chemical class of compounds, aminoguanidine indoles, designed to act specifically at 5 HT4 receptors in the GI tract:
A representative of a new chemical class of compounds, aminoguanidine indoles, designed to act specifically at 5 HT4 receptors in the GI tract:
CMOA 9CMOA 95
Pharmacologic Profile of TegaserodPharmacologic Profile of Tegaserod
Tegaserod, a partial agonist, displays high affinity for human 5-HT4 receptors (KB = 18 nM)
Tegaserod mimics action of 5-HT and potently stimulates intrinsic sensory neurons triggering the peristaltic reflex (EC50 5 nM)
Tegaserod has negligible affinity for 5-HT3
receptors (KB = 7,200 nM); therefore, it is devoid
of relevant 5-HT3 receptor antagonism
Tegaserod, a partial agonist, displays high affinity for human 5-HT4 receptors (KB = 18 nM)
Tegaserod mimics action of 5-HT and potently stimulates intrinsic sensory neurons triggering the peristaltic reflex (EC50 5 nM)
Tegaserod has negligible affinity for 5-HT3
receptors (KB = 7,200 nM); therefore, it is devoid
of relevant 5-HT3 receptor antagonism
CMOA 10CMOA 10
Tegaserod Triggers the Peristaltic ReflexTegaserod Triggers the Peristaltic Reflex
5
EnterocytesEnterocytes ECsECs
5-HT5-HT
ACh,Substance P
ACh,Substance P
VIP,PACAP, NOVIP,PACAP, NO
TegaserodTegaserod
CMOA 11CMOA 115
Neurotransmitter Release Induced by Tegaserod is Inhibited by Selective 5-HT4 Antagonist
Neurotransmitter Release Induced by Tegaserod is Inhibited by Selective 5-HT4 Antagonist
Means ± SE (n = 3 - 8)Grider et al. Gastroenterology 1998; 115: 370-380
f
mo
l /
10
0 m
g ·
min
Humanjejunum
Guinea pigcolon
Ratcolon
8
7
6
5
4
3
2
1
0
Substance PSubstance P
f
mo
l /
10
0 m
g ·
min
7
6
5
4
3
2
1
0Humanjejunum
Guinea pigcolon
Ratcolon
VIPVIP
8
Tegaserod alone
+ 5-HT3 antagonist
+ 5-HT4 antagonist
CMOA 12CMOA 12
1 10 100 1,0000
80
100
120
140
160
180
200
% o
f c
on
tro
l
Tegaserod concentration (nM)
Jin et al. Jin et al. J. Pharmacol. Exp. Ther.J. Pharmacol. Exp. Ther. 1999; 288: 93- 1999; 288: 93-9797
5
Tegaserod-Induced Propulsion in Guinea Pig Colon
Tegaserod-Induced Propulsion in Guinea Pig Colon
Means ± SEM (n = 3 - 4)
Velocity of propulsionVelocity of propulsion
CMOA 13CMOA 13
50 mm Hg50 mm HgColonColon
JejunumJejunum
IleumIleum
0 90
TegaserodTegaserod
MinutesMinutes
Nguyen et al. JPET. 1997;280:1270-1276.
5
Tegaserod Stimulates Canine Small Bowel and Colonic Motility After IV Tegaserod
Tegaserod Stimulates Canine Small Bowel and Colonic Motility After IV Tegaserod
CMOA 14CMOA 14
Distribution of colonic isotope at 30 minutes following IV administration of tegaserodDistribution of colonic isotope at 30 minutes following IV administration of tegaserod
Saline Vehicle 0.03 0.1 0.30
20
40
60
80
100
Nguyen et al. J. Pharmacol. Exp. Ther. 1997; 280: 1270-1276
5
RectosigmoidProximal Distal
Tegaserod dose (mg/kg)
Co
lon
ic c
on
ten
ts i
n r
eg
ion
, %
Tegaserod Stimulates CanineColonic Motility and Transit
Tegaserod Stimulates CanineColonic Motility and Transit
Means ± SEM (n = 6)
CMOA 15CMOA 15
Effect of Tegaserod on Gastrointestinal Transit in Healthy Subjects
Effect of Tegaserod on Gastrointestinal Transit in Healthy Subjects
Means ± SEM (n = 12)
*P < .05 vs placebo, †P < .005 vs placebo
Perc
en
t of
Con
trol
-60
-40
-20
0
20
40
60
Gastricemptying
rate
Small boweltransit
time
**
†† Tegaserod 0.6 mg IV
Tegaserod 6 mg PO
Degen et al. Gastroenterology 2000; AGA Meeting, abstract
CMOA 16CMOA 16
Baseline 1 week0
20
40
60
80
100
Baseline 1 weekTegaserod Placebo
Col
onic
fil
ing,
%
Prather, et al. Gastroenterology. 2000.
Colonic Filling at 6 HoursEffect of Tegaserod in C-IBS
Colonic Filling at 6 HoursEffect of Tegaserod in C-IBS
CMOA 17CMOA 17
0
1
2
3
4
Baseline Week 1 Baseline Week 1
Geo
met
ric
Cen
ter
(48
ho
urs
)
Effect of Tegaserod on Colonic Transit in C-IBSEffect of Tegaserod on Colonic Transit in C-IBS
PlaceboPlacebo Tegaserod (2 mg b.i.d.)
Tegaserod (2 mg b.i.d.)
00
11
22
33
44
55StoolStool
Prather et al. Gastroenterology 2000; 118: 463-468
5
*
Means ± S.E.M. (n = 12)*P < .05 vs baseline
Colonic localization of radiotracer
CMOA 18CMOA 185
Summary : Motor Effects of Tegaserod
Summary : Motor Effects of Tegaserod
Tegaserod mimics the physiologic response to serotonin released from enterochromaffin cells, triggering the peristaltic reflex
Tegaserod promotes motility throughout theGI tract in animals and humans
Tegaserod mimics the physiologic response to serotonin released from enterochromaffin cells, triggering the peristaltic reflex
Tegaserod promotes motility throughout theGI tract in animals and humans
CMOA 19CMOA 195
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects
– Effects on motility– Effects on visceral sensitivity
Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions
Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects
– Effects on motility– Effects on visceral sensitivity
CMOA 20CMOA 20
Visceral Sensitivity End-Points for Preclinical Studies in Small AnimalsVisceral Sensitivity End-Points for
Preclinical Studies in Small Animals
Single afferent fiber recordings
Pseudo-affective measurements:
– Animal behavior, eg, withdrawal, writhing
– Abdominal contractions
– Drop in arterial BP (under anesthesia)
Single afferent fiber recordings
Pseudo-affective measurements:
– Animal behavior, eg, withdrawal, writhing
– Abdominal contractions
– Drop in arterial BP (under anesthesia)
CMOA 21CMOA 21
Static stimulus-response curve
(single afferent unit in dorsal
root S2 )
Submaximal firing rates at 50 mm Hg
Static stimulus-response curve
(single afferent unit in dorsal
root S2 )
Submaximal firing rates at 50 mm Hg
Ruehl et al. Ruehl et al. Neurogastroenterol. MotNeurogastroenterol. Mot. 1998; 10: 219-222. 1998; 10: 219-222
Effect of Tegaserod on Visceral Sensitivity in Cats
Effect of Tegaserod on Visceral Sensitivity in Cats
5
1 ms
CMOA 22CMOA 22
Schikowski et al. Gastroenterology 1999; 116: A643
5
Dose-Dependent Inhibition by Tegaserod of Afferent Nerve Activity to Rectal Distension in Cats
Dose-Dependent Inhibition by Tegaserod of Afferent Nerve Activity to Rectal Distension in Cats
100
80
60
40
20
0 0 0.3 0.6 0.9 1.2 1.5
Tegaserod dose (mg/kg IV)
EC50 = 0.7 mg/kg
Effect inhibited by 5-HT4 antagonistEffect inhibited by 5-HT4 antagonist
**
*
* *
Means ± SD (n = 9)*P < .05
% o
f ve
hic
le c
on
tro
l
Firing rate at 50 mm Hg distensionFiring rate at 50 mm Hg distension
CMOA 23CMOA 23
Tegaserod Inhibits Abdominal Contractions in Response to Colorectal Distension in Awake Rats
Tegaserod Inhibits Abdominal Contractions in Response to Colorectal Distension in Awake Rats
*
*
5
0
10
20
30
40
50
0 15 30 45 60Balloon pressure, mm Hg
Ab
do
min
al c
on
tra
cti
on
s/5
min
ute
s Control
Vehicle
Tegaserod 1 mg/kg IP
Mean ± SEM (n = 7)
*P < .05 versus vehicle
Coelho, et al. Gastroenterology. 2000;118:A835.
CMOA 24CMOA 24
Summary : Sensory Effects of Tegaserod
Summary : Sensory Effects of Tegaserod
During colorectal distension:
Tegaserod reduces visceral afferent firingin cats via stimulation of 5-HT4 receptors
Tegaserod inhibits visceral discomfort / pain in rats
During colorectal distension:
Tegaserod reduces visceral afferent firingin cats via stimulation of 5-HT4 receptors
Tegaserod inhibits visceral discomfort / pain in rats
CMOA 25CMOA 25
SummarySummary
Serotonin and its 5-HT4 receptors are involved
in motor, secretory, and sensory processes in the GI tract
Tegaserod, a partial 5-HT4 receptor agonist,
stimulates GI motor functions, and inhibits visceral sensitivity
Tegaserod may influence the sensorimotor dysfunctions and symptoms of constipation-predominant IBS
Serotonin and its 5-HT4 receptors are involved
in motor, secretory, and sensory processes in the GI tract
Tegaserod, a partial 5-HT4 receptor agonist,
stimulates GI motor functions, and inhibits visceral sensitivity
Tegaserod may influence the sensorimotor dysfunctions and symptoms of constipation-predominant IBS