Indoloquinolizidine-Peptide Hybrids as Multiple Agonists for D1 and D2 Dopamine Receptors

Multiple-specificity ligands are considered promising pharmacological tools that may show higher efficacy in the treatment of diseases for which the modulation of a single target is therapeutically inadequate. We prepared a set of novel ligands for D-1 and D-2 dopamine receptors by combining two indolo[2,3-a]quinolizidine scaffolds with various tripeptide moieties. The binding and functional properties of these molecules were determined by radioligand binding studies in brain striatum membranes and by intracellular cAMP production assays in cells expressing different dopamine receptor subtypes. Some indoloquinolizidine-peptide hybrids, mainly with the trans configuration, showed dual agonist activity at both D-1 and D-2 dopamine receptors and may therefore be useful for testing the therapeutic potential of multivalent drugs on these targets.