Abstract
A series of cis and trans 3β-aryl-2-carbomethoxy-6-azabicyclo[3.2.1] octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the β-aryl group, IC50=452 nM) displayed a potency that is in the same range as cocaine (IC50=459 nM) itself.
| Original language | English |
|---|---|
| Pages (from-to) | 1383-1391 |
| Number of pages | 9 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2004 |
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Keywords
- 6-Azabicyclo[3.2.1]octane
- Cocaine
- Dopamine uptake
- Normorphan analogues
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors. / Quirante, Josefina; Vila, Xavier; Bonjoch, Josep; Kozikowski, Alan P.; Johnson, Kenneth M.
In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 6, 15.03.2004, p. 1383-1391.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors
AU - Quirante, Josefina
AU - Vila, Xavier
AU - Bonjoch, Josep
AU - Kozikowski, Alan P.
AU - Johnson, Kenneth M.
PY - 2004/3/15
Y1 - 2004/3/15
N2 - A series of cis and trans 3β-aryl-2-carbomethoxy-6-azabicyclo[3.2.1] octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the β-aryl group, IC50=452 nM) displayed a potency that is in the same range as cocaine (IC50=459 nM) itself.
AB - A series of cis and trans 3β-aryl-2-carbomethoxy-6-azabicyclo[3.2.1] octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the β-aryl group, IC50=452 nM) displayed a potency that is in the same range as cocaine (IC50=459 nM) itself.
KW - 6-Azabicyclo[3.2.1]octane
KW - Cocaine
KW - Dopamine uptake
KW - Normorphan analogues
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UR - http://www.scopus.com/inward/citedby.url?scp=1542331633&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2004.01.019
DO - 10.1016/j.bmc.2004.01.019
M3 - Article
C2 - 15018911
AN - SCOPUS:1542331633
VL - 12
SP - 1383
EP - 1391
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 6
ER -