Abstract
3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT. These SAR studies provide further evidence for the varied binding requirements of structurally diverse tropane-based ligands and support future studies to elucidate DAT binding requirements in relation to cocaine-like behavioral endpoints.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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Carrier Proteins / metabolism*
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Caudate Nucleus / metabolism
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Dopamine / metabolism
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Dopamine Plasma Membrane Transport Proteins
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In Vitro Techniques
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins / metabolism*
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Models, Molecular
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Nerve Tissue Proteins*
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins
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Protein Binding
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Putamen / metabolism
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Radioligand Assay
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Rats
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Receptor, Muscarinic M1 / metabolism
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Serotonin / metabolism
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Serotonin Plasma Membrane Transport Proteins
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Structure-Activity Relationship
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Symporters / metabolism*
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Tropanes / chemical synthesis*
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Tropanes / chemistry
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Tropanes / metabolism
Substances
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Carrier Proteins
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Dopamine Plasma Membrane Transport Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Norepinephrine Plasma Membrane Transport Proteins
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Receptor, Muscarinic M1
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Serotonin Plasma Membrane Transport Proteins
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Slc6a2 protein, rat
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Slc6a3 protein, rat
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Slc6a4 protein, rat
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Symporters
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Tropanes
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Serotonin
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Dopamine
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Norepinephrine