Synthesis and characterization of selective dopamine D 2 receptor antagonists

Abstract

A series of indole compounds have been prepared and evaluated for affinity at D 2-like dopamine receptors using stably transfected HEK cells expressing human D 2, D 3, or D 4 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 D 2 and D 3 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 D 2 receptor compared to the human D 3 receptor, and (c) bind with low affinity to the human D 4 dopamine receptor subtype. Binding at sigma (σ) receptor subtypes, σ 1 and σ 2, were also examined and it was found that the position of the methoxy group on the indole was pivotal in both (a) D 2 versus D 3 receptor selectivity and (b) affinity at σ 1 receptors. Adenylyl cyclase studies indicate that our indole compounds with the greatest D 2 receptor selectivity are neutral antagonists at human D 2 dopamine receptor subtypes. With stably transfected HEK cells expressing human D 2 (hD 2-HEK), these compounds (a) have no intrinsic activity and (b) attenuated quinpirole inhibition of adenylyl cyclase. The D 2 receptor selective compounds that have been identified represent unique pharmacological tools that have potential for use in studies on the relative contribution of the D 2 dopamine receptor subtypes in physiological and behavioral situations where D 2-like dopaminergic receptor involvement is indicated.