To evaluate a previously suggested "dopamine (DA) D2 receptor agonist pharmacophore model" the N-propyl derivatives (1S,2S)-5-hydroxy-1-methyl-2-propylaminotetralin [(1S,2S)-3)] and trans-(+/-)-5-hydroxy-3-methyl-2-propylaminotetralin [(+/-)-4] were synthesized and their conformational preferences were studied by molecular mechanics calculations. The new compounds were evaluated for affinity to striatal DA D2 receptors labelled by [3H]spiroperidol and [3H]N-propylnorapomorphine. In comparison to the corresponding N,N-dipropyl derivatives, compounds (1S,2S)-3 and (+/-)-4 more readily adopt pharmacophore conformations and have higher affinity for DA D2 receptors. Thus, the pharmacophore model for C5-oxygenated 2-aminotetralins appears to be accurate. The DA D2 receptor binding affinities of a series of C1- or C3-methyl substituted 5- or 7-hydroxy-2-dipropylaminotetralin derivatives were also determined to enable a comparison of three different modes of superposition, of 7- and 5-hydroxylated 2-aminotetralin derivatives. The results show that the relative spatial positions of the C1- and C3-methyl groups resulting from the various superpositions of 5- and 7-hydroxylated regioisomers differ and the fact that the bulk of a methyl group may be readily accepted by the receptor does not necessarily indicate that additional bulk may be tolerated. Consequently, a definitive choice of mode of superposition of 5- and 7-hydroxylated regioisomers can not be made at present and has to wait until the binding site itself has been better defined.