Mesulergine and its 1,20-N,N-bidemethylated metabolite interact directly with D1- and D2-receptors.

Mesulergine (CU 32-085), an 8 alpha-aminoergoline, has been reported to influence striatal dopamine turnover in a time-dependent biphasic manner, suggesting initial dopamine antagonistic and late dopamine agonistic effects. To clarify whether these opposing in vivo effects are due to a metabolic conversion in vivo or reflect mixed antagonist/agonist effects expressed at different dose levels, mesulergine and a 1,20-N,N-bidemethylated metabolite, identified in rat urine, were investigated in functional dopamine receptor models. Dopamine-sensitive adenylate cyclase in homogenates of rat striatum and modulation of electrically evoked tritium overflow from rat striatal slices previously labelled with [3H]choline were used as tests for D1- and D2-receptors, respectively. Mesulergine was found to antagonise D1-receptor responses at micromolar, and D2-receptor responses at nanomolar concentrations. In contrast, the bidemethylated metabolite of mesulergine stimulated both D1- and D2-receptors at micromolar and nanomolar concentrations, respectively. These in vitro results suggest that at dopamine receptors, mesulergine has antagonistic effects and that the late agonistic effects seen in vivo are mostly due to metabolic conversion into a potent dopaminomimetic drug.