Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT1A receptor
| Autor: | Rolf Johansson, Lars Johansson, Ingeborg Csöregh, Martin Nylöf, Sverker Hanson, Nina Mohell, Eva Hammarberg, Bo-Ragnar Tolf, Charlotte Ahlgren, Anita Westlind-Danielsson, Gun Torell Svantesson, Robert Leideborg, Gunnar Nordvall, Eva Jerning, Seth-Olov Thorberg |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Models Molecular Intrinsic activity Stereochemistry In Vitro Techniques Crystallography X-Ray Transfection Chemical synthesis Hippocampus Cell Line Rats Sprague-Dawley chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Drug Discovery Radioligand Cyclic AMP Animals Humans Receptor Serotonin 5-HT2A Carboxylate Receptor Pyrans Cerebral Cortex 8-Hydroxy-2-(di-n-propylamino)tetralin Chemistry Receptors Dopamine D2 Receptors Dopamine D1 Absolute configuration Stereoisomerism Corpus Striatum Benzopyran Rats Serotonin Receptor Agonists Receptors Serotonin Molecular Medicine Receptors Serotonin 5-HT1 |
| Zdroj: | Journal of medicinal chemistry. 43(15) |
| ISSN: | 0022-2623 |
| Popis: | 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-HT1A 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), D2 (rat striatum), D2A (human cloned), and 5-HT2A (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-HT1A receptor. High-affinity compounds with high selectivity for the 5-HT1A 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-HT1A receptor than the corresponding (S)-enantiomers. In the present series of compounds, both full and partial agonists were found. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|