Ring expansions of tetrahydroprotoberberines and related dibenzo[c,g]azecines modulate the dopamine receptor subtype affinity and selectivity.
The affinities of tetrahydroprotoberberines for dopamine receptors dramatically decrease after cleaving the central C-N bond to the analogous ten-membered dibenzo[c,g]azecines [1]. In the present work, we also synthesized eleven-membered homologues of these heterocycles and measured the affinities of the resulting dibenzazaundecenes and their underlying homoberberines for human dopamine receptors as well as the cytotoxic effects of all target compounds on human glia cells. The tetracyclic iso-C-homoberberine-derivatives revealed to be D(4)-selective antagonists, while all other active compounds showed a significant D(1)/D(5) selectivity. Distances in energy-minimized conformations were measured in order to explain our findings.
Schulze
Maria
M
Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universität Jena, Jena, Germany.
Siol
Oliver
O
Meise
Werner
W
Lehmann
Jochen
J
Enzensperger
Christoph
C
D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; C014845:berbine