Inhibition of potassium-stimulated acetylcholine release from rat brain cortical slices by two high-affinity analogs of vesamicol.

In this work, we investigated the effects of two structural analogs of the drug vesamicol, which inhibits the vesicular acetylcholine (ACh) transport, on the potassium-stimulated release of ACh from rat brain cortical slices. These vesamicol analogs, 4-aminobenzovesamicol (ABV) and (trans)-cyclohexovesamicol (transDec), were almost as potent as vesamicol in inhibiting the evoked release of ACh from cortex slices. Similar to vesamicol, the presence of these analogues inhibited the ability of ACh newly-synthesized from [3H]choline to become releasable. However, vesamicol's action was reversible, while ABV and transDec caused a persistent block of this [3H]ACh release. In addition, vesamicol did not affect the release of pre-stored [3H]ACh, but ABV and transDec partially inhibited the release of [3H]ACh in this condition, suggesting that the two latter drugs may alter some of the steps posterior to the entry of [3H]ACh into synaptic vesicles. The rank order of potency for these drugs to reduce ACh release (vesamicol = transDec > ABV) is close to the rank order for inhibition of ACh vesicular transport (transDec > vesamicol > ABV), but is completely different from the order of affinities of these drugs for the vesamicol receptor (ABV > transDec > > vesamicol). These results suggest that although these two vesamicol analogs are able to block ACh release due to their effects on the vesicular transport system, they may have other unexpected actions not shared by vesamicol.