Structure activity relationship of homochiral 7-substituted 1-aminoindans as 5-HT1A receptor ligands

A series of homochiral 7-substituted 1-aminoindans was prepared by means of asymmetric reductive amination from racemic 7-substituted 1-indanones via E-imines and E-imine/enamine mixtures, respectively, and subjected to 5-hydroxytryptamine (5-HT) receptor subtype binding studies. The ee's of the title compounds were determined by HPLC of the corresponding Mosher's amides and range from 96 to 99.9%. The absolute configuration was elucidated by means of correlation CD spectroscopy. On the basis of the pK1 values obtained from various test systems, structure activity relationships have been established with respect to the absolute configuration, degree of N-alkylation, and the type of 7-substituents. The tested 1-aminoindans show the highest affinity to the 5-HT1A receptor, with decreasing magnitude for the 5-HT2A, 5-HT1D, and 5-HT2C receptors. The highest affinities for the 5-HT1A receptor were observed for the R-(-)-7-propoxy-1-(di-n-propylamino)indan hydrochloride (R-(-)-30). S,S'-(+)-7-benzylamido-1-(1-phenylethylamino)indan hydrochloride [S,S'-(+)-19] and R-(-)-7-methoxy-1-(di-n-propylamino)indan hydrogenembonate (R-(-)-29) with pK1 = 7.07 +/- 0.19, 6.40 +/- 0.09, and 6.22 +/- 0.10, respectively, in comparison to 8-OH-DPAT with pK1 = 8.70 +/- 0.30. Nearly all other compounds showed low affinity at all 5-HT receptors tested. The three above mentioned ligands were tested on HeLa cells (cell line HA6) expressing recombinant human 5-HT1A receptors for their effects on forskolin-stimulated cAMP accumulation in intact cells. Both the di-n-propylamino substituent bearing R-(-)-30 and R-(-)-29 acted as efficacious agonists with a pEC50 value of 5.89 +/- 0.20 for R-(-)-30 compared to 5-HT with a pEC50 value of 8.06 +/- 0.14, S,S'-(+)-19 with the 1-phenylethylamino substituent was devoid of intrinsic activity up to the highest tested concentration (10 microM).