Substituted ergolines: potential antipsychotics with unique profile. II. Neurochemical characterization.

A series of lumilysergol and lysergol derivatives were studied with a number of neurochemical methods. The compounds investigated showed heterogenous profiles on receptor binding tests. They were mostly active on D-2 receptors, but some alpha-1, alpha-2 and 5-HT-2 affinity could also be demonstrated. None of the drugs showed remarkable D-1 activities tested on basal and DA-stimulated adenylate cyclase (AC) enzyme in vitro. On the basis of the effects of the drugs on the mouse whole brain monoamine neurotransmitter and metabolite levels and neurotransmitter biosynthesis rates along with the receptor binding data we conclude that their actions are mainly related to the central dopaminergic system(s). The 2-halo-lumilysergole derivatives were less potent than the 2-halo-lysergoles with respect to their dopaminergic actions. We found the substitution at position 8 to be substantial to achieve agonistic or antagonistic properties, and, interestingly, 2,8-dihalo-lysergoles have proven to be DA agonists. The neurochemical findings are in good agreement with the behavioral results presented in the accompanying paper. We confirmed the behavioral data in that there are two subgroups among 2-halo-lysergoles possessing antipsychotic activity with opposite effects on DA receptors.