Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors

Robert H. Mach, Joseph R. Jackson, Robert R. Luedtke, Kathryn J. Ivins, Perry B. Molinoff, Richard L. Ehrenkaufer

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.

Original languageEnglish
Pages (from-to)423-430
Number of pages8
JournalJournal of Medicinal Chemistry
Volume35
Issue number3
DOIs
StatePublished - 1 Feb 1992

Fingerprint

Serotonin 5-HT2 Receptors
Spiperone
Alkylation
Dopamine
Amides
Positron-Emission Tomography
Nitrogen
Carbon

Cite this

Mach, Robert H. ; Jackson, Joseph R. ; Luedtke, Robert R. ; Ivins, Kathryn J. ; Molinoff, Perry B. ; Ehrenkaufer, Richard L. / Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors. In: Journal of Medicinal Chemistry. 1992 ; Vol. 35, No. 3. pp. 423-430.
@article{eb748915fc9c4eeaa92f9456a22d8903,
title = "Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors",
abstract = "Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.",
author = "Mach, {Robert H.} and Jackson, {Joseph R.} and Luedtke, {Robert R.} and Ivins, {Kathryn J.} and Molinoff, {Perry B.} and Ehrenkaufer, {Richard L.}",
year = "1992",
month = "2",
day = "1",
doi = "10.1021/jm00081a002",
language = "English",
volume = "35",
pages = "423--430",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors. / Mach, Robert H.; Jackson, Joseph R.; Luedtke, Robert R.; Ivins, Kathryn J.; Molinoff, Perry B.; Ehrenkaufer, Richard L.

In: Journal of Medicinal Chemistry, Vol. 35, No. 3, 01.02.1992, p. 423-430.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors

AU - Mach, Robert H.

AU - Jackson, Joseph R.

AU - Luedtke, Robert R.

AU - Ivins, Kathryn J.

AU - Molinoff, Perry B.

AU - Ehrenkaufer, Richard L.

PY - 1992/2/1

Y1 - 1992/2/1

N2 - Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.

AB - Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.

UR - http://www.scopus.com/inward/record.url?scp=0026511048&partnerID=8YFLogxK

U2 - 10.1021/jm00081a002

DO - 10.1021/jm00081a002

M3 - Article

C2 - 1531364

AN - SCOPUS:0026511048

VL - 35

SP - 423

EP - 430

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -