Dopamine receptor binding of a novel dibenzodioxazocine derivative, EGYT-2509.
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.
Gyüre
K
K
Szentendrei
T
T
Kanyicska
B
B
Fekete
M I
MI
Rónai
A Z
AZ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism; D003989:Dibenzoxazepines / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism
D014150:Antipsychotic Agents; D003989:Dibenzoxazepines; D011954:Receptors, Dopamine; D013134:Spiperone; C049176:EGYT 2509; D000262:Adenylyl Cyclases