RT Journal Article
SR Electronic
T1 TTA-P2 is a Potent and Selective Blocker of T-type Calcium Channels in Rat Sensory Neurons and a Novel Antinociceptive Agent
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.073205
DO 10.1124/mol.111.073205
A1 WonJoo Choe
A1 Richard B Messinger
A1 Emily Leach
A1 Veit-Simon Eckle
A1 Aleksandar Obradovic
A1 Reza Salajegheh
A1 Vesna Jevtovic-Todorovic
A1 Slobodan M. Todorovic
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/08/05/mol.111.073205.abstract
AB Several agents that are preferential T-type calcium (T-channel) blockers have shown promise as being effective in alleviating acute and chronic pain, suggesting an urgent need to identify even more selective and potent T-channel antagonists. We used small, acutely dissociated dorsal root ganglion (DRG) cells of adult rats to study the in vitro effects of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), a derivative of 4-aminomethyl-4-fluoropiperdine, on T-currents, as well as other currents known to modulate pain transmission. We found that TTA-P2 potently and reversibly blocked DRG T-currents with an IC50 of 100 nM and stabilized channel in the inactive state, while high-voltage-activated (HVA) calcium and sodium currents were 100-1,000-fold less sensitive to channel blocking effects. In in-vivo studies, we found that intraperitoneal (i.p.) injections of 5 or 7.5 mg/kg of TTA-P2 reduced pain responses in mice in phases 1 and 2 of the formalin test. Furthermore, TTA-P2, at 10 mg/kg i.p., selectively and completely reversed thermal hyperalgesia in diabetic rats treated with streptozocin, but had no effect on the nociceptive response of healthy animals. The anti-hyperalgesic effects of TTA-P2 in diabetic rats were completely abolished by administration of oligonucleotide antisense for CaV3.2 isoform of T-channels.Thus, TTA-P2 is not only the most potent and selective blocker of T-channels in sensory neurons yet described, but also demonstrates the potential for the pharmacological effectiveness of this approach in addressing altered nociceptive responses in animal models of both inflammatory and neuropathic pain.