Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives

Suhong Zhang, Sari E Izenwasser, Dean Wade, Liang Xu, Mark L. Trudell

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with the 3α-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3α-analogue, while the 3β-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3α-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.

Original languageEnglish
Pages (from-to)7943-7952
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number23
DOIs
StatePublished - Dec 1 2006

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Tropanes
Derivatives
Serotonin Plasma Membrane Transport Proteins
Ether
Nitrogen
Atoms
8-azabicyclo(3.2.1)octane
vanoxerine

Keywords

  • Cocaine
  • Dopamine transporter
  • Serotonin transporter
  • Tropane

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives. / Zhang, Suhong; Izenwasser, Sari E; Wade, Dean; Xu, Liang; Trudell, Mark L.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 23, 01.12.2006, p. 7943-7952.

Research output: Contribution to journalArticle

@article{74aaf892e04d4e33a274550b2a0b5587,
title = "Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives",
abstract = "A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with the 3α-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3α-analogue, while the 3β-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3α-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.",
keywords = "Cocaine, Dopamine transporter, Serotonin transporter, Tropane",
author = "Suhong Zhang and Izenwasser, {Sari E} and Dean Wade and Liang Xu and Trudell, {Mark L.}",
year = "2006",
month = "12",
day = "1",
doi = "10.1016/j.bmc.2006.07.051",
language = "English",
volume = "14",
pages = "7943--7952",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "23",

}

TY - JOUR

T1 - Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives

AU - Zhang, Suhong

AU - Izenwasser, Sari E

AU - Wade, Dean

AU - Xu, Liang

AU - Trudell, Mark L.

PY - 2006/12/1

Y1 - 2006/12/1

N2 - A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with the 3α-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3α-analogue, while the 3β-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3α-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.

AB - A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with the 3α-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3α-analogue, while the 3β-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3α-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.

KW - Cocaine

KW - Dopamine transporter

KW - Serotonin transporter

KW - Tropane

UR - http://www.scopus.com/inward/record.url?scp=33750052304&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750052304&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2006.07.051

DO - 10.1016/j.bmc.2006.07.051

M3 - Article

C2 - 16905323

AN - SCOPUS:33750052304

VL - 14

SP - 7943

EP - 7952

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 23

ER -