A series of analogues 2a-i related to 3-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-8-(1H-indol-2-ylmethyl)-3,8-dia zabicyclo[3.2.1]octane (1) in which the 3,8-diazabicyclo[3.2.1]octane core was replaced by 3,6-diazabicyclo[3.1.1]heptane ring system has been synthesized and evaluated for their ability to inhibit DA reuptake into striatal nerve endings (synaptosomes). Biological data showed that compound 2a, the closest analogue of lead 1, possessed an increased reuptake inhibition activity over 1 (2a, Ki = 5.5 nM). Replacement of the indole ring with bioisosteric aromatic rings-benzothiophene (2b), benzofurane (2c), or indene (2d)-resulted, with the exception of 2d, in a double digit nanomolar activity. Changing the indenyl moiety of 2d with simplified aryl groups led to compounds 2e-h which displayed a similar or slightly decreased activity with respect to the ground term. Naphthalene derivative (2i) demonstrated a weaker activity than aromatic analogues. © 2007 Elsevier Ltd. All rights reserved.
3-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-6-substituted-3,6-diazabicyclo[ 3.1.1]heptanes as novel potent dopamine uptake inhibitors / Loriga, G.; Ruiu, S.; Manca, I.; Murineddu, G.; Dessi, C.; Pani, L.; Pinna, G. A.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 15:11(2007), pp. 3748-3755. [10.1016/j.bmc.2007.03.035]
3-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-6-substituted-3,6-diazabicyclo[ 3.1.1]heptanes as novel potent dopamine uptake inhibitors
Pani L.;
2007
Abstract
A series of analogues 2a-i related to 3-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-8-(1H-indol-2-ylmethyl)-3,8-dia zabicyclo[3.2.1]octane (1) in which the 3,8-diazabicyclo[3.2.1]octane core was replaced by 3,6-diazabicyclo[3.1.1]heptane ring system has been synthesized and evaluated for their ability to inhibit DA reuptake into striatal nerve endings (synaptosomes). Biological data showed that compound 2a, the closest analogue of lead 1, possessed an increased reuptake inhibition activity over 1 (2a, Ki = 5.5 nM). Replacement of the indole ring with bioisosteric aromatic rings-benzothiophene (2b), benzofurane (2c), or indene (2d)-resulted, with the exception of 2d, in a double digit nanomolar activity. Changing the indenyl moiety of 2d with simplified aryl groups led to compounds 2e-h which displayed a similar or slightly decreased activity with respect to the ground term. Naphthalene derivative (2i) demonstrated a weaker activity than aromatic analogues. © 2007 Elsevier Ltd. All rights reserved.
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