3-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-6-substituted-3,6-diazabicyclo[3.1.1]heptanes as novel potent dopamine uptake inhibitors.
A series of analogues 2a-i related to 3-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-8-(1H-indol-2-ylmethyl)-3,8-diazabicyclo[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, K(i)=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.
Loriga
Giovanni
G
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, I-07100 Sassari, Italy.
Ruiu
Stefania
S
Manca
Ilaria
I
Murineddu
Gabriele
G
Dessi
Christian
C
Pani
Luca
L
Pinna
Gérard A
GA
D000818:Animals; D001681:Biological Assay; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects
C418117:3-(2-(bis(4-fluorophenyl)methoxy)ethyl)-8-(1H-indol-2-ylmethyl)-3,8-diazabicyclo(3.2.1)octane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018765:Dopamine Uptake Inhibitors; D006536:Heptanes; D007211:Indoles