- Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT(1A) receptor
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A series of new enantiomerically pure 3-amino-3,4-dihydro-2H-1- benzopyrans (3-aminochromans) has been synthesized from (R)- and (S)-5- methoxy-3-amino-3,4-dihydro-2H-1-benzopyran. The absolute configuration of the respective (R)- and (S)-enantiomers was deduced from X-ray crystallography of (R)-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1- benzopyran, (R)-9a. Various 5-substituents were introduced via palladium- catalyzed carbonylation of N-substituted 3-amino-5- trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran. The effect of N- and 5-substitution on affinity for the 5-HT(1A) receptor was evaluated in competition experiments using rat hippocampal membranes and [3H]8-OH-DPAT as radioligand. Selected compounds were also tested for their affinity to the D1 (rat striatum), D1 (rat striatum), D(2A) (human cloned), and 5-HT(2A) (rat cortex) receptors. The intrinsic activity of the compounds was evaluated by measuring their effect on VIP-stimulated cAMP production in GH4ZD10 cells stably transfected with the 5-HT(1A) receptor. High-affinity compounds with high selectivity for the 5-HT(1A) receptor were found among structures substituted with carboxylate esters, amides, and ketones in the 5-position. Primary and secondary amines bound with lower affinity than tertiary amines. Larger substituents were well-tolerated by the receptor, but the smaller N- ethyl-N-isopropyl bound with lower affinity. Generally, the (R)-enantiomers displayed higher affinity for the 5-HT(1A) receptor than the corresponding (S)-enantiomers. In the present series of compounds, both full and partial agonists were found.
- Hammarberg, Eva,Nordvall, Gunnar,Leideborg, Robert,Nyl?f, Martin,Hanson, Sverker,Johansson, Lars,Thorberg, Seth-Olov,Tolf, Bo-Ragnar,Jerning, Eva,Svantesson, Gun Torell,Mohell, Nina,Ahlgren, Charlotte,Westlind-Danielsson, Anita,Cs?regh, Ingeborg,Johansson, Rolf
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- Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2
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Novel compounds combining a 5-HT1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affin
- Hatzenbuhler, Nicole T.,Baudy, Reinhardt,Evrard, Deborah A.,Failli, Amedeo,Harrison, Boyd L.,Lenicek, Steven,Mewshaw, Richard E.,Saab, Annmarie,Shah, Uresh,Sze, Jean,Zhang, Minsheng,Zhou, Dahui,Chlenov, Michael,Kagan, Michael,Golembieski, Jeannette,Hornby, Geoffrey,Lai, Margaret,Smith, Deborah L.,Sullivan, Kelly M.,Schechter, Lee E.,Andree, Terrance H.
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scheme or table
p. 6980 - 7004
(2009/11/30)
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- Synthesis of enantiomerically pure 3-aminochroman derivatives
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Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from L-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from D-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.
- Usse, Stephanie,Pave, Gregoire,Guillaumet, Gerald,Viaud-Massuard, Marie-Claude
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p. 1689 - 1694
(2007/10/03)
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