title: Synthesis and characterization of selective dopamine D2 receptor antagonists.
abstract: 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 D2-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 D2 receptor subtype with nanomolar affinity, (b) be 10- to 100-fold selective for the human D2 receptor compared to the human D3 receptor, and (c) bind with low affinity to the human D4 dopamine receptor subtype. Binding at sigma (sigma) receptor subtypes, sigma1 and sigma2, 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 sigma1 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.
authors.affiliation: Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO 63110, USA.
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McElveen
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D011994:Recombinant Proteins; D000262:Adenylyl Cyclases