Synthesis, electrophysiological properties and analysis of structural requirements of a novel class of antiarrhythmic agents with potassium and calcium channel blocking properties.
Class III antiarrhythmic agents have been shown to prevent reentrant arrhythmias but also to be responsible for initiating arrhythmias characterised by afterdepolarizations and triggered activities. By combining potassium and calcium channel antagonistic actions, as with BRL-32872 (1), it might be possible to reduce the incidence of proarrhythmias albeit retaining antiarrhythmic efficacy. In the present study we synthesised and tested for their electrophysiological activity in guinea pig papillary muscle a wide panel of analogues of BRL-32872. Some qualitative relationships between compound structure and the inhibitory effect on the rapidly activating component of the delayed rectifier potassium current and/or the L-type calcium current will be presented. New derivatives depicting bell-shaped dose-response curves on action potential duration may therefore represent novel agents for improved antiarrhythmic therapy.
Nadler
G
G
SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France. Guy_Nadler@sbphrd.com
Faivre
J F
JF
Forest
M C
MC
Cheval
B
B
Martin
M
M
Souchet
M
M
Gout
B
B
Bril
A
A
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D051668:Delayed Rectifier Potassium Channels; D004594:Electrophysiology; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D015394:Molecular Structure; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D051668:Delayed Rectifier Potassium Channels; D007202:Indicators and Reagents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C094198:BRL 32872