Muscarinic Receptors: Rationale for OAB Treatment

1
Muscarinic Receptors Rationale for OAB Treatment

• Dr. Michael Ruggieri, Sr.
• Department of Urology
• Temple University, Philadelphia, PA

2
Bladder Anatomy and Function
CNS inhibitory/stimulatory
M2 M3 Muscarinic Receptors
Sympathetic-Hypogastric Nerve
ParasympatheticPelvic Nerve
Bladder Detrusor Smooth muscle
SomaticPundal Nerve
Internal Sphincter Smooth Muscle
Extramural Skeletal Muscle
Wein, Exp. Opin. Invest. Drugs 10(1) 65-83, 2001
3
Muscarinic Receptors

• Muscarinic receptors are identified primarily on
  the basis of the effect and relative potency of
  selective agonistsand antagonists
• Five subtypes have been identified.
• In peripheral tissues the role of three are well
  established
• M1 - Autonomic ganglia of secretory glands,
  presynaptically in bladder
• M2 - Heart and bladder (smooth muscle) and
  presynaptically in bladder
• M3 - Smooth muscle and secretory glands
• All 3 also found in the CNS

4
Normal Contractions
Receptor Activation
Ga proteins
PI-PLC
IP3
IP3 Receptor
SR calcium Release
Calmodulin Activation
MLC Kinase
MLC
Muscle Contraction
5
Normal Contractions (PI-PLC Inhibition)
Receptor Activation
Ga proteins
PLD
RhoA
DAG
ROCK
PKC
CPI-17
MLC
MLC Phosphatase
Muscle Contraction
Decreased Agonist Potency
1. Braverman, A.S., Tibb, A.S. and Ruggieri, M.R.
J Pharmacol Exp Ther, 316 869-874, 2006.
6
Normal Contractions (ROCK Inhibition)
Receptor Activation
Ga proteins
PI-PLC
IP3
IP3 Receptor
SR calcium Release
Calmodulin Activation
MLC Kinase
MLC
Muscle Contraction
Decreased Agonist Potency
1. Braverman, A.S., Tibb, A.S. and Ruggieri, M.R.
J Pharmacol Exp Ther, 316 869-874, 2006.
7
Denervated1 or M3 Desensitized By Repeated CRC2
(PI-PLC Inhibition)
Receptor Activation
Gß? proteins (M2)
Ga proteins (M1,3,5)
PLA2 PLD
PI3 Kinase
RGS-4
PIP3
PI-PLC
PC-PLC
PKG-I
PLD
RhoA
Arachidonic Acid
Atypical PKC
Ca Channels
ROCK
IP3
DAG
cAMP
PKC
PKA and PKG
IP3 Receptor
Non-selective Cation channels
Ca
MYPT1
CPI-17
SR calcium Release
Calmodulin Activation
Ca
?
Ca Dependent K channel
MLC Kinase
MLC
MLC Phosphatase
Relaxation
Muscle Contraction
No Change in Agonist Potency
1. Braverman, AS, Doumanian, LR and Ruggieri, MR
J Pharmacol Exp Ther, 316 875-880, 2006. 2.
Schneider T, Hein P, Michel MC. J Pharmacol Exp
Ther, 308(1)47-53,2004.
8
Denervated1 or M3 Desensitized By Repeated CRC2
(ROCK Inhibition)
Receptor Activation
Ga proteins
PI-PLC
IP3
IP3 Receptor
SR calcium Release
Calmodulin Activation
MLC Kinase
MLC
Muscle Contraction
Decreased Agonist Potency
1. Braverman, AS, Doumanian, LR and Ruggieri, MR
J Pharmacol Exp Ther, 316 875-880, 2006. 2.
Fleichman M, Schneider T, Fetscher C, Michel MC.
J Pharmacol Exp Ther, 308(1)54-8, 2004.
9
M2 / M3 in the Bladder Wall
Section of Bladder Wall
Umbrella Cell
Bladder lumen
Endothelium
Lamina Propria
M2 Muscarinic Receptor
M3 Muscarinic Receptor
Smooth Muscle
10
Urothelial Muscarinic Mechanism
Muscarinic Receptor
Muscarinic Receptor
ACh
ATP
NO
M2, M3
P2X,P2Y
Sensory nerves
Spinal Cord
11
Muscarinic Receptors (M2, M3) Sub-urothelium
Inflammatory mediators
12
Increased bladder capacity by antimuscarinics
depends on C-fiber afferents

• Yokoyama, O. et al. J Urol, 174, 2032-2036,
  2005.
• Suzuki, M et al. Eur J Pharmacol, 512, 61-66,
  2005

13
Overactive Bladder (OAB)

• Chronic syndrome with debilitating symptoms
  defined as
• Urgency, with or without
• urgency incontinence,
• often accompanied
• by frequency and nocturia

14
Pathophysiology of Urgency
Activation of sensory neurons
Bladder distension
15
Antimuscarinic Agents
Tolterodine
Oxybutynin
H3C
CH3
COOH
OH
H
CH
OH
CH3
C2H5
N
O

• HO

CH
H3C
C
CH2
C
C
N
CH2
C
O

• HCl

COOH
CH3
C2H5
OH
Trospium Chloride
O
N
C
OH
O
Solifenacin
Darifenacin
O
N
O
NH2
O
O
N
N
16
Muscarinic Binding Studies
M2
M3
M3 M2
Agent


1.3
Trospium3
9.2
9.3
3.2
8.0
8.5
Tolterodine1
12.6
7.8
8.9
Oxybutynin1

12.6
6.9
8.0
Solifenacin2
50.1
7.4
9.1
Darifenacin1

1. Wallis RM, Napier CM. Life Sci.
199964395-401.2. Ikeda K, et al.
Naunyn-Schmiedebergs Arch Pharmacol.
2002366(2)97-103. 3. Napier C, et al. Proc
ICS. 2002445 (abstract).
17
Muscarinic Receptor Balanced Selectivity M3M2
1.0 Equipotent
M3 selective
M3M2 Selectivity
Relatively M3 selective
Relatively equipotent (M2/M3)
Trospium
Tolterodine
Solifenacin
Oxybutynin
Darifenacin
1.3
3.2
12.6
12.6
50.1
1. Wallis RM, Napier CM. Life Sci.
199964395-401.2. Ikeda K, et al.
Naunyn-Schmiedebergs Arch Pharmacol.
2002366(2)97-103. 3. Napier C, et al. Proc
ICS. 2002445 (abstract).
18
Inhibitory Function of Antimuscarinics
Urothelium-derived ATP
ACH Release from nerves and urothelium(?)
Stretch of detrusor cells
Antimuscarinic agents
Increased mygenic activity (M2,M3)
Intramural afferent nerves activation (M2)
Suburothelial afferent nerves activation (M2,M3)
Afferent nerve
Urgency/micturition
Andersson K. Lancet Neurol 2004 3 46-53
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Summary

• Overactive Bladder is an imbalance of afferent
  and efferent input
• Both M2 and M3 may play a role in the sensory and
  myogenic pathways
• The role of systemic and intravesical
  administration of drugs requires further study

20
Bladder Anatomy and Function
21
Muscarinic Receptors
22
Urothelium
Basal membrane
IC
Lamina propria
Muscularis mucosae
IC
Detrusor
C-fiber
Ad fiber
C-fiber
IC interstitial cells
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URGENCY
Urothelium
ATP
ACh
PGs
NO -
Basal membrane
IC
TKs
VIP-
PACAP-
Lamina propria
Muscularis mucosae
IC
Detrusor
C-fiber
Ad fiber
C-fiber
IC interstitial cells
K-E Andersson, 2005