BIOISOSTERIC APPROACH IN THE DESIGN OF NEW DOPAMINERGIC SEROTONERGIC LIGANDS/

Dopaminergic and serotonergic ligands are widely applied in the therap y of some severe diseases in humans connected to the malfunctioning of the corresponding membrane receptors within the CNS. However, no phar maceuticals of this type with an ideal therapeutic index have been syn thesized so far and there is a constant need of producing new dopamine rgic/serotonergic ligands with improved properties especially with reg ard to undesirable side effects expressed after a prolonged therapy. D opaminergic/serotonergic ratio turned out to be important for. fine tu ning of pharmacological profile of new ligands. Employing a bioisoster ic approach, we have synthesized numerous quinoxalinediones, benztriaz oles, benzimidazoles and 2-substituted benzimidazoles as potential dop aminergic and/or mixed dopaminergic/serotonergic compounds. With this purpose, benzimidazole and its derivatives were incorporated into phen ylethylamine, 3- and 4-substituted phenylethylpiperidine, substituted 4-arylpiperazine and semirigid 2-aminotetralin frame and the resulting ligands were checked for the binding affinity at the D-1 and D-2 dopa mine and 5-HT1A serotonin receptors in radioligand binding assays in v itro. Synaptosomal membranes prepared from bovine caudate nuclei and h ippocampi served as a source of the dopamine and serotonin receptors, respectively. [H-3]SCH 23390 (D-1 receptor-selective), [H-3]spiperone (D-2 receptor-selective) and 8-OH-[H-3]DPAT (5-HT1A receptor-selective ) were employed as radioligands in competition binding assays. Propert ies of substituents introduced into position 2 of benzimidazole ring, as well as the nature of the frame into which benzimidazole pharmacoph ore was incorporated have been shown to determine ligand binding affin ity, mode of action and receptor preference, i.e. dopaminergic/seroton ergic affinity ratio. Benzimidazolyl-2-thione and benztriazole derivat ives were the most potent dopaminergic/serotonergic ligands. Molecular ab initio calculations of the electronic properties of pharmacophoric entities of the new ligands revealed different electron density distr ibution around the benzene ring in the active and inactive ligands. It can be assumed that this difference influences the properties of pi-p i: interactions in a receptor-ligand complex. The results are discusse d in comparison with the data of other authors working on similar topi cs.