Stereoselective Syntheses of the trans-Decahydroquinoline-5-carboxylic Acid Epimers. Diastereomeric Zwitterionic Probes of 7-Aminobutyric Acid Related Biological Properties in Vitro and in Vivo

Donald T. Witiak, Raymond J. Patch, S. J. Enna, Yiu K. Fung

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The syntheses of the 50 and 5a epimers of trans-(4aα,8aß)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian- 2-ylidene) octahydro- 2 (1H)-quinolinone (13) to afford the 5α-(l,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5ß-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GabaA and Gababreceptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to Gabaaand Gababreceptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalJournal of Medicinal Chemistry
Volume29
Issue number1
DOIs
StatePublished - Jan 1 1986

Fingerprint

Aminobutyrates
Convulsants
gamma-Aminobutyric Acid
GABA Antagonists
Imides
Picrotoxin
GABA Receptors
Diazepam
Seizures
Central Nervous System
Binding Sites
Brain
decahydroquinoline-5-carboxylic acid
In Vitro Techniques
carbostyril

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Stereoselective Syntheses of the trans-Decahydroquinoline-5-carboxylic Acid Epimers. Diastereomeric Zwitterionic Probes of 7-Aminobutyric Acid Related Biological Properties in Vitro and in Vivo. / Witiak, Donald T.; Patch, Raymond J.; Enna, S. J.; Fung, Yiu K.

In: Journal of Medicinal Chemistry, Vol. 29, No. 1, 01.01.1986, p. 1-8.

Research output: Contribution to journalArticle

@article{b34c50beb021438e94f1072cecfc0fcd,
title = "Stereoselective Syntheses of the trans-Decahydroquinoline-5-carboxylic Acid Epimers. Diastereomeric Zwitterionic Probes of 7-Aminobutyric Acid Related Biological Properties in Vitro and in Vivo",
abstract = "The syntheses of the 50 and 5a epimers of trans-(4aα,8a{\ss})-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian- 2-ylidene) octahydro- 2 (1H)-quinolinone (13) to afford the 5α-(l,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5{\ss}-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GabaA and Gababreceptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to Gabaaand Gababreceptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.",
author = "Witiak, {Donald T.} and Patch, {Raymond J.} and Enna, {S. J.} and Fung, {Yiu K.}",
year = "1986",
month = "1",
day = "1",
doi = "10.1021/jm00151a001",
language = "English (US)",
volume = "29",
pages = "1--8",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

TY - JOUR

T1 - Stereoselective Syntheses of the trans-Decahydroquinoline-5-carboxylic Acid Epimers. Diastereomeric Zwitterionic Probes of 7-Aminobutyric Acid Related Biological Properties in Vitro and in Vivo

AU - Witiak, Donald T.

AU - Patch, Raymond J.

AU - Enna, S. J.

AU - Fung, Yiu K.

PY - 1986/1/1

Y1 - 1986/1/1

N2 - The syntheses of the 50 and 5a epimers of trans-(4aα,8aß)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian- 2-ylidene) octahydro- 2 (1H)-quinolinone (13) to afford the 5α-(l,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5ß-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GabaA and Gababreceptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to Gabaaand Gababreceptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.

AB - The syntheses of the 50 and 5a epimers of trans-(4aα,8aß)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian- 2-ylidene) octahydro- 2 (1H)-quinolinone (13) to afford the 5α-(l,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5ß-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GabaA and Gababreceptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to Gabaaand Gababreceptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.

UR - http://www.scopus.com/inward/record.url?scp=0022601112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022601112&partnerID=8YFLogxK

U2 - 10.1021/jm00151a001

DO - 10.1021/jm00151a001

M3 - Article

C2 - 3001304

AN - SCOPUS:0022601112

VL - 29

SP - 1

EP - 8

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -