Dopamine/serotonin receptor ligands, part III [1]: synthesis and biological activities of 7, 7'-alkylene-bis-6, 7, 8, 9, 14, 15-hexahydro-5H-benz[d]indolo[2, 3-g]azecines -- application of the bivalent ligand approach to a novel type of dopamine receptor antagonist.

A series of 7, 7'-alkylene-bridged dimers(7a-e) of the benz [d]indolo[3, 2-f]azecine derivative LE300 was synthesized. Affinity and functional activity at dopamine D(1) and D(2) receptors were estimated by radioligand binding and a functional Ca(2+) assay. All the new bivalent ligands showed significant binding affinities to both D(1) and D(2) receptors with an optimal distance between the two monomeric recognition units of 6 methylene moieties. The D(1)/D(2)-selectivity pattern was dependent on the spacer length. No (7a, b) or only moderate (7c-e) functional activity was detected for all bivalent compounds by measuring the inhibition of agonist-induced increase in intracellular Ca(2+).