Hydroxylated analogs of mexiletine as tools for structural-requirements investigation of the sodium channel blocking activity.
[2-(2-Aminopropoxy)-1,3-phenylene]dimethanol 1 and 4-(2-aminopropoxy)-3-(hydroxymethyl)-5-methylphenol 2, two dihydroxylated analogs of mexiletine - a well known class IB anti-arrhythmic drug - were synthesized and used as pharmacological tools to investigate the blocking-activity requirements of human skeletal muscle, voltage-gated sodium channel. The very low blocking activity shown by newly synthesized compounds corroborates the hypothesis that the presence of a phenolic group in the para-position to the aromatic moiety and/or benzylic hydroxyl groups on the aromatic moiety of local anesthetic-like drugs impairs either the transport to or the interaction with the binding site in the pore of Na(+) channels.
Catalano
Alessia
A
Department of Medicinal Chemistry, University of Bari, Bari, Italy. a.catalano@farmchim.uniba.it
Carocci
Alessia
A
Cavalluzzi
Maria M
MM
Di Mola
Antonia
A
Lentini
Giovanni
G
Lovece
Angelo
A
Dipalma
Antonella
A
Costanza
Teresa
T
Desaphy
Jean-François
JF
Conte Camerino
Diana
D
Franchini
Carlo
C
D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D006900:Hydroxylation; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine