Dopamine receptor binding of a novel dibenzodioxazocine derivative, EGYT-2509

Abstract

The binding of novel dibenzodioxazocine derivatives to rat striatal dopamine receptors was studied in vitro, using 3H-spiperone as radioligand. The biochemical-pharmacological characteristics of the effect of a selected representative, EGYT-2509 are discussed in details. The parameters of specific spiperone binding to rat striatal membrane preparation (KD = 0.550 nM, Bmax = 465 fmole/mg protein) as well as the displacing potencies of known dopamine receptor ligands matched closely the corresponding values in the literature. Using 0.4 nM radioligand, a Ki value of 404 nM was obtained for EGYT-2509; the binding of the drug had a minor serotonergic component. EGYT-2509 behaved as a dopamine receptor antagonist in all functional in vitro biochemical-pharmacological tests (striatal adenylate cyclase, striatal dopamine release, prolactin release from pituitary) performed previously. The drug exhibited a marked preference for adenylate cyclase-coupled (D1) dopamine receptors, followed by the 3H-spiperone displacing potency at striatal receptors. It was a rather weak antagonist both at striatal dopamine autoreceptors and at the receptors controlling prolactin release. Finally, when comparing the structure-activity relationships obtained with dibenzo-dioxazocines in the dopamine receptor binding assay with the relative pharmacological potencies of a structurally related neuroleptic group, i.e. of phenothiazines, a definite parallelism could be demonstrated.