Synthesis and characterization of selective dopamine D 2 receptor antagonists

Suwanna Vangveravong, Elizabeth McElveen, Michelle Taylor, Jinbin Xu, Zhude Tu, Robert T. Luedtke, Robert H. Mach

Research output: Contribution to journalArticle

33 Scopus citations


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.

Original languageEnglish
Pages (from-to)815-825
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number3
StatePublished - 1 Feb 2006


  • D -like dopamine receptors
  • Dopamine receptor antagonists
  • Indoles
  • Sigma receptors

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