Synthesis and structure-active relationship of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline anticonvulsants.
We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticonvulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported analogues. This novel series of isoquinolines was designed on the basis of well defined structure-active relationship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2) mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-1-(4'-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6d) that displayed significant anticonvulsant activity. Computational studies helped to rationalize these obtained pharmacological results.
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy. rgitto@unime.it
Rosaria
R
Gitto
Laura
L
De Luca
Stefania
S
Ferro
Stefano
S
Agnello
Emilio
E
Russo
Giovanbattista
G
De Sarro
Alba
A
Chimirri
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
D000927:Anticonvulsants; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline