Synthesis and D2 Dopaminergic Activity of Pyrrolidinium, Tetrahydrothiophenium, and Tetrahydrothiophene Analogues of Sulpiride

Marc W. Harrold, Raye Ann Wallace, Tahira Farooqui, Lane J. Wallace, Norman Uretsky, Duane Miller

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6, 7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H] acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 μM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D 2binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D 2receptor.

Original languageEnglish (US)
Pages (from-to)874-880
Number of pages7
JournalJournal of Medicinal Chemistry
Volume32
Issue number4
DOIs
StatePublished - Apr 1 1989
Externally publishedYes

Fingerprint

Sulpiride
Dopamine Antagonists
Amines
Corpus Striatum
Spiperone
Apomorphine
Chlorpromazine
Dopamine Receptors
Acetylcholine
Nitrogen
Pharmaceutical Preparations
tetrahydrothiophene

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and D2 Dopaminergic Activity of Pyrrolidinium, Tetrahydrothiophenium, and Tetrahydrothiophene Analogues of Sulpiride. / Harrold, Marc W.; Wallace, Raye Ann; Farooqui, Tahira; Wallace, Lane J.; Uretsky, Norman; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 32, No. 4, 01.04.1989, p. 874-880.

Research output: Contribution to journalArticle

Harrold, Marc W. ; Wallace, Raye Ann ; Farooqui, Tahira ; Wallace, Lane J. ; Uretsky, Norman ; Miller, Duane. / Synthesis and D2 Dopaminergic Activity of Pyrrolidinium, Tetrahydrothiophenium, and Tetrahydrothiophene Analogues of Sulpiride. In: Journal of Medicinal Chemistry. 1989 ; Vol. 32, No. 4. pp. 874-880.
@article{15202b5a8ecc476489060377f99d557c,
title = "Synthesis and D2 Dopaminergic Activity of Pyrrolidinium, Tetrahydrothiophenium, and Tetrahydrothiophene Analogues of Sulpiride",
abstract = "All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6, 7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H] acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 μM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D 2binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D 2receptor.",
author = "Harrold, {Marc W.} and Wallace, {Raye Ann} and Tahira Farooqui and Wallace, {Lane J.} and Norman Uretsky and Duane Miller",
year = "1989",
month = "4",
day = "1",
doi = "10.1021/jm00124a024",
language = "English (US)",
volume = "32",
pages = "874--880",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Synthesis and D2 Dopaminergic Activity of Pyrrolidinium, Tetrahydrothiophenium, and Tetrahydrothiophene Analogues of Sulpiride

AU - Harrold, Marc W.

AU - Wallace, Raye Ann

AU - Farooqui, Tahira

AU - Wallace, Lane J.

AU - Uretsky, Norman

AU - Miller, Duane

PY - 1989/4/1

Y1 - 1989/4/1

N2 - All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6, 7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H] acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 μM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D 2binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D 2receptor.

AB - All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6, 7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H] acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 μM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D 2binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D 2receptor.

UR - http://www.scopus.com/inward/record.url?scp=0024478224&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024478224&partnerID=8YFLogxK

U2 - 10.1021/jm00124a024

DO - 10.1021/jm00124a024

M3 - Article

VL - 32

SP - 874

EP - 880

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -