Synthesis of 3-aryl-1-[(4-phenyl-1-piperazinyl)butyl]indazole derivatives and their affinity to 5-HT1A serotonin and dopamine D-1 receptors

Eight 3-arylindazole derivatives have been synthesized and their affinity t o 5-HT1A serotonin and D-1 dopamine receptors was investigated by radioliga nd analysis. Quantitative structure-activity relationships were studied usi ng the Free-Wilson model. An increase in affinity to dopamine D-1 receptors within substituents Br > Cl > CH3 at the 5-position of the 3-arylindazole molecule has been observed. Addition of a chlorine atom to the ortho-positi on the of phenyl ring let to even highes activity. Replacement of the hydro gen atom at the first position of the 3-arylindazole on the (phenylpiperazi ne)butyl substituent caused an increase of affinity and did not change the trends of affinity dependence on structure. An inverse dependence on the st ructure of the studied compounds was observed for the serotonin 5-HT1A rece ptors. Compounds containing a methyl group at the 5-position of molecule we re more active than compounds containing halogens. A chlorine atom at the o rtho-position of the phenyl ring decreased affinity. Replacement of the hyd rogen atom at the first position of the molecule on the phenylpiperazine)bu tyl substituent led to an increase in affinity. Selectivity of the studied compounds varied within a wide range. Generally, the presence of the 3-aryl -indazole fragment in the new buspirone analogues increased their affinity to dopamine receptors and reduced their affinity to serotonin receptors. Co mpounds containing a bromine atom in the 3-arylindazole moiety may be promi sing ligands for D-1 receptors.