Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT1A receptor

Citation
E. Hammarberg et al., Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT1A receptor, J MED CHEM, 43(15), 2000, pp. 2837-2850
Citations number
35
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
43
Issue
15
Year of publication
2000
Pages
2837 - 2850
Database
ISI
SICI code
0022-2623(20000727)43:15<2837:SON53D>2.0.ZU;2-6
Abstract
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-i sopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran, (R)-9a. Various 5-sub stituents were introduced via palladium-catalyzed carbonylation of N-substi tuted 3-amino-5-trifluoromethanesulfonyloxy-3,4-dihydro- 2H-1-benzopyran. T he effect of N- and 5-substitution on affinity for the 5-HT1A receptor was evaluated in competition experiments using rat hippocampal membranes and [H -3]8-OH-DPAT as radioligand. Selected compounds were also tested for their affinity to the D-1 (rat striatum), D-2 (rat striatum), D-2A (human cloned) , and 5-HT2A (rat cortex) receptors. The intrinsic activity of the compound s was evaluated by measuring their effect on VIP-stimulated cAMP production in GH(4)ZD10 cells stably transfected with the 5-HT1A receptor. High-affin ity compounds with high selectivity for the 5-HT1A receptor were found amon g structures substituted with carboxylate esters, amides, and ketones in th e 5-position. Primary and secondary amines bound with lower affinity than t ertiary amines. Larger substituents were well-tolerated by the receptor, bu t 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 fu ll and partial agonists mere found.