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. (C) 2009 Elsevier Ltd. All rights reserved.