title: A novel non-phenolic dibenzazecine derivative with nanomolar affinities for dopamine receptors.
abstract: Dibenzazecines are a novel class of dopamine receptor antagonists, characterized by their high affinities as well as their tendency for D(1) selectivity. Hitherto, the most active dibenzazecines were phenolic in nature; a 3-OH substituent was found to result in the highest affinities. However, the phenolic nature of these compounds mostly renders them unsuitable for in vivo application, due to the poor pharmacokinetic profile, imparted by the phenolic group. A novel dibenzazecine derivative was prepared, with methylenedioxy moiety, connecting C(2) amd C(3), instead of the 3-OH group. The newly synthesized derivative 3 showed high affinities similar to the lead LE404, displaying nanomolar affinities for all dopamine receptor subtypes. Its dibrominated derivative 4, though exhibiting almost a fivefold decrease in affinities, still displayed nanomolar ones for all dopamine receptors, except for D(4) . In a functional Ca(2+) assay, both compounds 3 and 4 were found to possess antagonistic properties towards the dopamine receptors.
authors.affiliation: Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität Jena, Philosophenweg 14, D-07743 Jena.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.forename: Shams
authors.initials: S
authors.lastname: Eldin AbulAzm
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Enzensperger
mesh_terms: D003984:Dibenzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011954:Receptors, Dopamine / Q000737:chemistry* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003984:Dibenzazepines; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1