T-type channel blocking properties and antiabsence activity of two imidazo[1,2-b]pyridazine derivatives structurally related to indomethacin.
It is presently unclear whether the antiseizure effects exerted by NSAIDs are totally dependent on COX inhibition or not. To clarify this point we investigated whether 7-methyl-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (DM2), two imidazo[1,2-b]pyridazines structurally related to indomethacin (IDM) but ineffective in blocking COXs, retain IDM antiabsence activity. When administered by intraperitoneal injection in WAG/Rij rats, a rat strain which spontaneously develops SWDs, both DM1 and DM2 dose-dependently suppressed the occurrence of these seizures. Importantly, these compounds were both more potent in suppressing SWD occurrence than IDM. As T-type channel blockade is considered a mechanism of action common to many antiabsence drugs we explored by whole cell patch clamp electrophysiology in stably transfected HEK-293 the effect of DM1 and DM2 on Ca(V)3.1 channels, the T-type channel subtype preferentially expressed in ventrobasal thalamic nuclei. Both these compounds dose-dependently suppressed the currents elicited by membrane depolarization in these cells. A similar T-type blocking effect was also observed when the cells were exposed to IDM. In conclusion, DM1 and DM2 whilst inactive on COXs, are potent antiabsence drugs. This suggests that compounds with structural features typical of NSAIDs may exert antiepileptic activity independently from COX inhibition and possibly by a direct interaction with T-type voltage-dependent Ca(2+) channels.
Rimoli
Maria Grazia
MG
Department of Pharmaceutical and Toxicological Chemistry, Faculty of Pharmacy, Federico II University of Naples, Via Domenico Montesano 49, 80131 Naples, Italy.
Russo
Emilio
E
Cataldi
Mauro
M
Citraro
Rita
R
Ambrosino
Paolo
P
Melisi
Daniela
D
Curcio
Annalisa
A
De Lucia
Salvatore
S
Patrignani
Paola
P
De Sarro
Giovambattista
G
Abignente
Enrico
E
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains
C540451:6-methoxy-2-phenylimidazo(1,2-b)pyridazine-3-carboxylic acid; C540450:7-methyl-2-phenylimidazo(1,2-b)pyridazine-3-carboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D007093:Imidazoles; D011724:Pyridazines; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin