Novel tacrine derivatives that block neuronal calcium channels Original Research Article

A new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) derivatives were synthesized and their effects on 45Ca2+ entry into bovine adrenal chromaffin cells stimulated with dimethylphenylpiperazinium (DMPP) or K+, studied. At 3 μM, compound 1 did not affect 45Ca2+ uptake evoked by DMPP. Compounds 14, 15 and 17 inhibited the effects of DMPP by 30%. Compounds 3, 9 and tacrine blocked the DMPP signal by about 50%. Compounds 5 and 12 were the most potent blockers of DMPP-stimulated 45Ca2+ entry (90%); the rest of the compounds inhibited the effects of DMPP by 70–80%. Compounds 1, 3, 4, 8, 10, 11, 13, 16, 17 and tacrine inhibited 45Ca2+ uptake induced by K+ about 20%. Compounds 6, 14 and 15 inhibited the K+ effects by 10% or less. Compounds 7, 9, 12 and 18 blocked the K+ signal by 30% and, finally, compounds 2 and 5 inhibited the K+-induced 45Ca2+ entry by 50%. None of the new compounds was as effective as diltiazem (IC50=0.03 μM) in causing relaxation of the rat aorta precontracted with 35 mM K+; the most potent was compound 7 (IC50=0.3 μM). Compounds 5, 6, 8, 9, 10 and 13 had IC50s around 10 μM and compounds 3, 4, 11 and 12 around 20 μM. Blockade of Ca2+ entry through neuronal voltage-dependent Ca2+ channels, without concomitant blockade of vascular Ca2+ channels, suggests that some of these compounds might exhibit neuroprotectant effects but not undesirable hemodynamic effects.