Electrostatic surface potential calculation on several new halogenated benzimidazole-like dopaminergic ligands

Abstract

We examined the effects of the electron density distribution (electrostatic surface potential; ESP) of several new benzimidazole-type ligands on their binding affinity for the D 1 and D 2 dopamine receptors (DAR). Receptors were prepared from synaptosomal membranes of bovine caudate nuclei. [ 3 H]SCH 23390 and [ 3 H]spiperone were used as specific radiolabels for the D 1 and D 2 receptors, respectively. The ESP of these compounds was calculated using Gaussian 98 W software. Calculations performed with known dopaminergic ligands showed that the electron density charge in the aromatic ring of these compounds favors a higher binding affinity for the D 2 DAR. This was confirmed by the synthesis of halogenated analogues of several known dopaminergic ligands. Halogenation resulted in an increase in the positive charge of the aromatic part of the molecule. None of the newly synthesized compounds was efficient in displacing [ 3 H]SCH 23390 from the D 1 DAR. The introduction of chlorine into the molecule led to a higher binding affinity for the D 2 DAR of the new ligands in comparison to both parent compounds and brominated ligands. This difference probably originates from the difference in the sizes of chlorine and bromine atoms, which could influence the interaction of a ligand with the receptor binding site. However, among the new ligands with bromine as a substituent, two compounds (8b and 10b) expressed a higher binding affinity and two of them (9b and 11b) a lower binding affinity for the D 2 DAR, when compared to unsubstituted parent compounds. These results indicate that the electrostatic surface potential of a ligand is an important factor in its interaction with the D 2 DAR and that this should be taken into account during design and synthesis of dopaminergic compounds.