Synthesis and monoamine transporter binding properties of 2,3-diaryltropanes.
Synthetic procedures were developed for the synthesis of 2beta,3beta- and 2alpha,3alpha-diaryltropanes. These compounds are analogues of the 3-aryltropane-2beta-carboxylic acid methyl ester class of monoamine uptake inhibitors, where the 2beta-carbomethoxy group has been replaced by an aryl group. The compounds were evaluated for inhibition of radioligand binding at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and 5-HTT, respectively). The results showed that the replacement of the 2beta-carbomethoxy group in the 3-aryltropane class with a 2beta-aryl group led to compounds possessing very similar monoamine transporter binding properties. However, the 2beta,3beta-diaryltropanes tended to be more potent at the DAT and more selective for the DAT relative to the NET and 5-HTT. One of the most interesting compounds was 3beta-(4-methylphenyl)-2beta-(4-methylphenyl)tropane (3d), which showed an IC50 of 1.23 nM at the DAT with 289- and 185-fold selectivity for the DAT relative to the NET and 5-HTT. The 2alpha,3alpha-diaryltropanes were much less potent at all three transporters than 2beta,3beta-diaryltropanes.
Kotturi
Sharadsrikar V
SV
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA.
Jiang
Songchun
S
Chang
An-Chih
AC
Abraham
Philip
P
Navarro
Hernán A
HA
Kuhar
Michael J
MJ
Carroll
F Ivy
FI
D000818:Animals; D001667:Binding, Competitive; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
C507034:3-(4-methylphenyl)-2-(4-methylphenyl)tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes