Synthesis and characterization of novel derivatives of 2-aminotetralins: Development of highly selective derivatives for the D3 receptor

2-Aminotetralin-type compounds have long been shown to have a high affinity for the D2 family of dopamine receptors. The D2 family is now known to inc lude D3 receptors, and recent results obtained with cloned dopamine recepto rs suggest that aminotetralin derivatives have preferential affinity for D3 as compared with D2 receptors. In our effort to develop selective ligands for the D3 receptor subtype, we explored the requirement in aminotetralins with dialkyl substitution on the amino moiety by changing one of the propyl group into a 2'-propynyl group and the other one into different alkyl-type substitutions. Our results demonstrated that the propyl group is not absol utely required as it can be replaced by the other groups without compromisi ng its activity and selectivity. Furthermore, two of the new analogs in the ir racemic mixtures showed more selectivity than the (+)-enantiomer of 7-OH -DPAT in binding to the D3 receptor when assayed under the same conditions. Unlike 7-OH-DPAT, the most selective compound, (+/-)-6, exhibited no locom otor stimulation at the highest dose tested. Our study thus indicated that D3 receptor selective compounds might have opposite effects on locomotor ac tion as compared with D2 receptor specific compounds.