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Antimyotonic actions of new chiral sodium channel, blockers
PharmacologicaI Research Communications, Vol. 20, Supplement II, 1988 ANTIMY~IC
111
ACTICNS OF NEW CHIRAL SODIUM CHANNEL, BIXgCKERS.
D. Conte Camerino, V. Tortorella, C. Franchini and D. Tricarico Pharmacobiology and Medicinal Chemistry Dept., University of Bari, Italy. Key words: Skeletal-muscle, myotonia, Na + channels, chiral agents Recently highly use-dependent antiarrhythmic drugs such as tocainide and mexiletine have been proposed for the treatment of all myotonias. Nevertheless relatively high concentrations of tocainide are needed to suppress experimental (Dengler and Rudel, 1979) and human myotonias and the treatment response and
the
side effects
are
dose-dependent
(Streib,
1987). In the present study the antimyotonic effects of some chiral analogs of tocainide (S- (+)phenylalanil-N- (2 methyl, 4 Cl-phenil )amide (I ) and S- (+)phenylalanil-N- (p.Clbenzil )amide (II )), synthesized and resolved in our laboratories, (Bettoni et ai,1987) have been tested "in vitro" on rat extensor digitorum longus fibers. ~asurements of m~mbreme potentials and excitability were made at 30°C with standard two microelectrodes methodology in presence of increasing concentrations(10-400 ~M) of each analog, alone, or after incubation of the preparation with anthracene-9-carboxylic acid, a potent myotonia inducer. The membrane resting potentials was not affected but both the enantiomers dose-dependently altered the action potential (AP) (incmease of threshold current and AP duration; decrease of AP latency and overshoot; block of fiber repetitive activity). Moreover I (50 ~M) and II (i00 ~M) completely abolished both the myotonic after discharge and repetitive firing, produced by 9AC. On the other hand, it has been reported that no less than 250 ~
tocainide was needed to
suppress myotonia in vitro (Dengler and Rudel, 1979). The" alterations in AP variables without change in resting
potential suggest that the new
derivatives act on fast sodium channels. Their mechanism is presently under investigation on human myball (Supported by MPI 87 and MDA grant)o REFERENCES Bettoni G., Loiodice F., Tortorella V., Conte-Camerino D. Mambrini M. Ferranini E., Bryant S.H. (1987) J. Medicinal Chem. 30:1267-1270 Dengler R. and Rudel R. (1979) Arzneim-Forsch/Drug Res.:29, 270-273 Streib E.W. (1987) Muscle Nerv.: 10/2, 155-162
111
ACTICNS OF NEW CHIRAL SODIUM CHANNEL, BIXgCKERS.
D. Conte Camerino, V. Tortorella, C. Franchini and D. Tricarico Pharmacobiology and Medicinal Chemistry Dept., University of Bari, Italy. Key words: Skeletal-muscle, myotonia, Na + channels, chiral agents Recently highly use-dependent antiarrhythmic drugs such as tocainide and mexiletine have been proposed for the treatment of all myotonias. Nevertheless relatively high concentrations of tocainide are needed to suppress experimental (Dengler and Rudel, 1979) and human myotonias and the treatment response and
the
side effects
are
dose-dependent
(Streib,
1987). In the present study the antimyotonic effects of some chiral analogs of tocainide (S- (+)phenylalanil-N- (2 methyl, 4 Cl-phenil )amide (I ) and S- (+)phenylalanil-N- (p.Clbenzil )amide (II )), synthesized and resolved in our laboratories, (Bettoni et ai,1987) have been tested "in vitro" on rat extensor digitorum longus fibers. ~asurements of m~mbreme potentials and excitability were made at 30°C with standard two microelectrodes methodology in presence of increasing concentrations(10-400 ~M) of each analog, alone, or after incubation of the preparation with anthracene-9-carboxylic acid, a potent myotonia inducer. The membrane resting potentials was not affected but both the enantiomers dose-dependently altered the action potential (AP) (incmease of threshold current and AP duration; decrease of AP latency and overshoot; block of fiber repetitive activity). Moreover I (50 ~M) and II (i00 ~M) completely abolished both the myotonic after discharge and repetitive firing, produced by 9AC. On the other hand, it has been reported that no less than 250 ~
tocainide was needed to
suppress myotonia in vitro (Dengler and Rudel, 1979). The" alterations in AP variables without change in resting
potential suggest that the new
derivatives act on fast sodium channels. Their mechanism is presently under investigation on human myball (Supported by MPI 87 and MDA grant)o REFERENCES Bettoni G., Loiodice F., Tortorella V., Conte-Camerino D. Mambrini M. Ferranini E., Bryant S.H. (1987) J. Medicinal Chem. 30:1267-1270 Dengler R. and Rudel R. (1979) Arzneim-Forsch/Drug Res.:29, 270-273 Streib E.W. (1987) Muscle Nerv.: 10/2, 155-162