Submitted on April 24, 2008
Revised on June 2, 2008
Accepted on June 16, 2008
AMTB, a TRPM8 Channel Blocker: Evidence in Rats for Activity in Overactive Bladder and Painful Bladder Syndrome
Erin S.R. Lashinger, Matthew S. Steiginga, J. Paul Hieble, Lisa A. Leon, Scott D. Gardner, Rakesh Nagilla, Elizabeth A. Davenport, Bryan E. Hoffman, Nicholas J. Laping1, and Xin Su2*
1 GlaxoSmithKline
2 GloxoSmithKline
* To whom correspondence should be addressed. E-mail: xin.2.su{at}gsk.com.
The activation of the TRPM8 channel, a member of the large class of TRP ion channels has been reported to be involved in overactive bladder and painful bladder syndrome although an endogenous activator has not been identified. In this study, N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB) was evaluated as a TRPM8 channel blocker and used as a tool to evaluate the effects of this class of ion channel blocker on volume induced bladder contraction and nociceptive reflex responses to noxious bladder distension in the rat. AMTB inhibits icilin-induced TRPM8 channel activation as measured in a Ca++ influx assay, with a pIC50 of 6.23. In the anesthetized rat, IV administration of AMTB (3 mg/kg) decreased the frequency of volume induced bladder contractions, without reducing the amplitude of contraction. The nociceptive response was measured by analyzing both visceromotor reflex (VMR) and cardiovascular (pressor) responses to urinary bladder distension (UBD) under 1% isoflurane. AMTB (10 mg/kg) significantly attenuated reflex responses to noxious UBD to 5.42% and 56.51% of the maximal VMR response and pressor response, respectively. The ID50 value on VMR response was 2.42 ± 0.46 mg/kg. These results demonstrate that TRPM8 channel blocker can act on the bladder afferent pathway to attenuate the bladder micturition reflex and nociceptive reflex responses in the rat. Targeting TRPM8 channel may provide a new therapeutic opportunity for overactive bladder and painful bladder syndrome.
