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A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors
Author(s) -
Robaa Dina,
ElDin AbulAzm Shams,
Lehmann Jochen,
Enzensperger Christoph
Publication year - 2011
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201000317
Subject(s) - affinities , chemistry , moiety , substituent , receptor , binding affinities , stereochemistry , derivative (finance) , dopamine , dopamine receptor , dopamine receptor d2 , selectivity , combinatorial chemistry , biochemistry , neuroscience , financial economics , economics , biology , catalysis
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.