Dibenzazecine scaffold rebuilding--is the flexibility always essential for high dopamine receptor affinities?
The moderately flexible 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are known to be potent dopamine receptor antagonists, whereas the corresponding rigid dibenzo[d,g]quinolizines are inactive. We built the scaffolds of dibenzo[c,g], [c,f] and [d,f]azecines and together with their ring closed, more rigid precursors, evaluated the affinities for the human D(1)-D(5) receptors (radioligand binding) as well as the functionalities (calcium assay) and thus investigated the influence of annelation and conformative flexibility of these compounds on their affinity for human cloned dopamine receptors.
Schulze
Maria
M
Institut für Pharmazie, Lehtuhl für Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, 07743 Jena, Germany.
Müller
Franziska K U
FK
Mason
Jennifer M
JM
Görls
Helmar
H
Lehmann
Jochen
J
Enzensperger
Christoph
C
D002118:Calcium; D003001:Cloning, Molecular; D018492:Dopamine Antagonists / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008968:Molecular Conformation; D018583:Pliability; D011485:Protein Binding; D011807:Quinolizines / Q000737:chemistry*; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018492:Dopamine Antagonists; D006571:Heterocyclic Compounds; D011807:Quinolizines; D011954:Receptors, Dopamine; D002118:Calcium