Affect Piperidine Block of Neuronal Calcium Channels

The effects of local anesthetics were examined on a family of transiently expressed neuronal calcium channels. Fomocaine, a local anesthetic containing a morpholine ring, preferentially blocked (Y,~ channels (Ki = 100 PM), and had a lower affinity (3to 15fold) for (Y,~, (Y,~, and cz,c channels. Block was incompletely reversible, followed I:1 kinetics, and did not affect steady-state inactivation properties. Fomocaine block was sensitive to the concentration of permeant ion and enhanced in the presence of external pore blockers, suggesting a site of action in the conducting pathway. Flecainide, which carries a piperidine ring, and the diphenylbutylpiperidine antipsychotic, penfluridol, caused qualitatively similar block, suggesting that morpholine rings are compatible with the piperidine receptor site. In contrast, procaine, which contains an alkyl chain, caused reversible low affinity block of the different calcium channels (K,, values between 2 and 5 mM) and was least effective on (Y, E and