Synthesis and characterization of selective dopamine D₂ receptor antagonists

A series of indole compounds have been prepared and evaluated for affinity at D₂-like dopamine receptors using stably transfected HEK cells expressing human D₂, D₃, or D₄ dopamine receptors. These compounds share structural elements with the classical D ₂-like dopamine receptor antagonists, haloperidol, N-methylspiperone, and benperidol. The compounds that share structural elements with N-methylspiperone and benperidol bind non-selectively to the D₂ and D₃ dopamine receptor subtypes. However, several of the compounds structurally similar to haloperidol were found to (a) bind to the human D ₂ receptor subtype with nanomolar affinity, (b) be 10- to 100-fold selective for the human D₂ receptor compared to the human D ₃ receptor, and (c) bind with low affinity to the human D₄ dopamine receptor subtype. Binding at sigma (σ) receptor subtypes, σ₁ and σ₂, were also examined and it was found that the position of the methoxy group on the indole was pivotal in both (a) D₂ versus D₃ receptor selectivity and (b) affinity at σ₁ receptors. Adenylyl cyclase studies indicate that our indole compounds with the greatest D₂ receptor selectivity are neutral antagonists at human D₂ dopamine receptor subtypes. With stably transfected HEK cells expressing human D₂ (hD₂-HEK), these compounds (a) have no intrinsic activity and (b) attenuated quinpirole inhibition of adenylyl cyclase. The D₂ receptor selective compounds that have been identified represent unique pharmacological tools that have potential for use in studies on the relative contribution of the D₂ dopamine receptor subtypes in physiological and behavioral situations where D₂-like dopaminergic receptor involvement is indicated.