Dihydropyridine receptor in rat brain labeled with [3H]nimodipine.

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Abstract
Receptor binding sites for 1,4-dihydropyridine (DHP) Ca2+ antagonists were characterized by using [3H]-nimodipine, a potent analog of nifedipine with cerebrovascular and neuro- and psychopharmacological properties. [3H]Nimodipine exhibited reversible and saturable binding to partially purified brain membranes. The equilibrium dissociation constant, Kd, was 1.11 nM and the maximal binding capacity, Bmax, was 0.50 pmol/mg of protein. The DHP receptor proved to be highly specific for various potently displacing DHP derivatives and discriminated between their optical isomers (stereoselectivity) with inhibition constants (Ki) in the nmol or even subnanomolar range. Structurally different Ca antagonists such as gallopamil (D-600), displayed much lower affinities, further substantiating the specificity of the receptor for DHP structures. The displacement potency of a series of DHP derivatives correlated well with that determined for inhibition of mechanical response in the intact smooth muscle over 5 orders of magnitude. [3H]Nimodipine binding may provide a molecular probe to elucidate the nature of the interaction of Ca2+ entry blockers with specific membrane-located receptor sites that may be associated with the putative Ca2+ channel. These receptor sites might well represent the loci of signaling events where the potent DHP exert their pharmacological action.