title: State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects.
abstract: 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.
authors.affiliation: Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France CNRS UMR5203, Montpellier, France INSERM, U661, Montpellier, France IFR3 Universités Montpellier I & II, Montpellier, France Clermont Université, Université d'Auvergne, Pharmacologie fondamentale et clinique de la douleur, BP 10448, F-63000 Clermont-Ferrand, France Inserm, U 766, F-63001 Clermont-Ferrand, France Merck Research Laboratories, West Point, PA, USA CHU Clermont-Ferrand, Service de Pharmacologie, F-63003 Clermont-Ferrand, France.
authors.forename: Amaury
authors.initials: A
authors.lastname: Francois
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kerckhove
authors.forename: Mathieu
authors.initials: M
authors.lastname: Meleine
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Alloui
authors.forename: Christian
authors.initials: C
authors.lastname: Barrere
authors.forename: Agathe
authors.initials: A
authors.lastname: Gelot
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.forename: Denis
authors.initials: D
authors.lastname: Ardid
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourinet
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C553486:2-(4-cyclopropylphenyl)-N-(1-(5-((2,2,2-trifluoroethyl)oxo)pyridin-2-yl)ethyl)acetamide; D044482:Benzeneacetamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011725:Pyridines