Highly selective chiral N-substituted 3α-[bis(4'- fluorophenyl)methoxy]tropane analogues for the dopamine transporter

Synthesis and comparative molecular field analysis

Michael J. Robarge, Gregory E. Agoston, Sari E Izenwasser, Theresa Kopajtic, Clifford George, Jonathan L. Katz, Amy Hauck Newman

Research output: Contribution to journalArticle

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Abstract

In a continuing effort to further characterize the role of the dopamine transporter in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3α-[bis(4'-fluorophenyl)methoxy]tropane (5) has been prepared as potential selective dopamine transporter ligands. These novel compounds displaced [3H]WIN 35,428 binding from the dopamine transporter in rat caudate putamen with K(i) values ranging from 13.9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly higher affinity for the dopamine transporter than the parent drug, 3α- (diphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective over muscarinic m1 receptors (dopamine transporter, K(i) = 11.8 nM; m1, K(i) = 11.6 nM) which could potentially confound the interpretation of behavioral data, for this compound and other members of this series. Thus, significant effort has been directed toward developing analogues that retain high affinity at the dopamine transporter but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affinity at the dopamine transporter (K(i) = 8.51 nM) while decreasing affinity at muscarinic receptors (K(i) = 576 nM) was achieved, resulting in 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S)N-(2-amino-3-methyl-n-butyl)-3α-[bis(4'- fluorophenyl)methoxy]tropane (10b) showing a 136-fold selectivity for the dopamine transporter versus muscarinic m1 receptors (K(i) = 29.5 nM versus K(i) = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q2 = 0.746) was used to accurately predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a visual representation of the chemical environment of the binding domain of the dopamine transporter, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors.

Original languageEnglish
Pages (from-to)1085-1093
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number6
DOIs
StatePublished - Mar 23 2000

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Tropanes
Dopamine Plasma Membrane Transport Proteins
Muscarinic M1 Receptors
Benztropine
Dopamine Uptake Inhibitors
Putamen
Muscarinic Receptors
Cocaine
Pharmaceutical Preparations
Cholinergic Agents
Rats
Pharmacology

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Highly selective chiral N-substituted 3α-[bis(4'- fluorophenyl)methoxy]tropane analogues for the dopamine transporter : Synthesis and comparative molecular field analysis. / Robarge, Michael J.; Agoston, Gregory E.; Izenwasser, Sari E; Kopajtic, Theresa; George, Clifford; Katz, Jonathan L.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 43, No. 6, 23.03.2000, p. 1085-1093.

Research output: Contribution to journalArticle

Robarge, Michael J. ; Agoston, Gregory E. ; Izenwasser, Sari E ; Kopajtic, Theresa ; George, Clifford ; Katz, Jonathan L. ; Newman, Amy Hauck. / Highly selective chiral N-substituted 3α-[bis(4'- fluorophenyl)methoxy]tropane analogues for the dopamine transporter : Synthesis and comparative molecular field analysis. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 6. pp. 1085-1093.
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