Synthesis and characterization of selective dopamine D2 receptor antagonists

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

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

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


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


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