Neuroleptics of the diphenylbutylpiperidine series are potent calcium channel inhibitors.
[3H]Fluspirilene, a neuroleptic molecule of the diphenylbutylpiperidine series, binds to skeletal muscle transverse tubule membranes with a high affinity corresponding to a Kd of 0.11 +/- 0.04 nM, A 1:1 stoichiometry was found between [3H]fluspirilene binding and the binding of (-)-[3H]desmethoxyverapamil [(-)[3H]D888], one of the most potent Ca2+ channel inhibitors. Ca2+ channel inhibitors such as D888, verapamil, gallopamil, bepridil, or diltiazem antagonize [3H]fluspirilene binding besides antagonizing (-)[3H]-D888 binding. Neuroleptics, especially those of the diphenylbutylpiperidine family, also antagonize both (-)[3H]D888 binding and [3H]fluspirilene binding. There is an excellent correlation between affinities found from [3H]fluspirilene binding experiments and those found from (-)[3H]D888 binding experiments. Analysis of the properties of these cross-inhibitions indicates that [3H]fluspirilene binds to a site that is not identical to that for phenylalkylamine derivatives (gallopamil, verapamil, diltiazem, and bepridil). Voltage-clamp experiments have shown that fluspirilene is an efficient inhibitor of the voltage dependent Ca2+ channel, achieving a half-maximal effect near 0.1-0.2 nM and nearly complete blockade at 1 nM. Fluspirilene blockade has little voltage dependence.
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism; D005484:Fluspirilene / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009132:Muscles / Q000378:metabolism / Q000648:ultrastructure; D011817:Rabbits; D013141:Spiro Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism
D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D007473:Ion Channels; D013141:Spiro Compounds; C043184:4-desmethoxyverapamil; D005484:Fluspirilene; D014700:Verapamil