Synthesis and evaluation of pharmacological profile of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides.
In previous studies we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives displaying potent anticonvulsant effects in different animal models of epilepsy. With the aim to deepen the structure-activity relationships (SAR) for this class of compounds and identify novel anticonvulsant agents we synthesized a series of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. The new compounds incorporate the main features of the above-mentioned anticonvulsants and a sulfonamide function capable to inhibit the enzyme carbonic anhydrase (CA, EC 4.2.1.1), which represents an attractive target in epilepsy. Pharmacological effects were evaluated in vivo against audiogenic seizures in DBA/2 mice and in vitro against several CA isoforms. Some of the new molecules showed anticonvulsant properties better than topiramate, but weak inhibitory activity and low selectivity in enzymatic assay.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy.
Ferro
Stefania
S
Agnello
Stefano
S
De Luca
Laura
L
De Sarro
Giovanbattista
G
Russo
Emilio
E
Vullo
Daniela
D
Supuran
Claudiu T
CT
Chimirri
Alba
A
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D007546:Isoquinolines; D002256:Carbonic Anhydrases