Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UMLS:C0022104 (
irritable bowel syndrome
)
8,033
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist
TTA
-A2 efficiently inhibits recombinant and native Ca(V)3.2 currents. Although
TTA
-A2 is a pan Ca(V)3 blocker, it demonstrates a higher potency for Ca(V)3.2 compared to Ca(V)3.1.
TTA
-A2 selectivity for T-type currents was demonstrated in sensory neurons where it lowered cell excitability uniquely on neurons expressing T-type channels. In vivo pharmacology in Ca(V)3.2 knockout and wild type mice reveal that
TTA
-A2-mediated antinociception critically depends on Ca(V)3.2 expression. The pathophysiology of
irritable bowel syndrome
(
IBS
) was recently demonstrated to involve Ca(V)3.2 in a rat model of this disease. Oral administration of
TTA
-A2 produced a dose-dependent reduction of hypersensitivity in an
IBS
model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of
TTA
-A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with
IBS
.
...
PMID:State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects. 2325 7
