Various pharmacophore models for potent σ(1) ligands specify a basic amino group flanked by two different hydrophobic regions in defined distances to the basic amine (distance 1 and distance 2, respectively). According to these models distance 1 of the potent spirocyclic σ(1) ligand 1 is too short. In order to find a new class of more potent σ(1) ligands and to verify the distance hypothesis of the pharmacophore models spirocyclic compounds 2 with an exocyclic amino group were designed and synthesized. The secondary amines 8 and 9 with N-benzyl residues are >100-fold less potent than the spirocyclic piperidine 1. However, the tertiary methylamines trans-11 and cis-11 represent potent σ(1) ligands with K(i)-values of 43 and 24 nM, respectively. Whereas one large benzyl moiety is required for high σ(1) receptor binding, a second large N-substituent is not tolerated by the σ(1) receptor protein. As a rule, cis-configured diastereomers with a longer distance 1 (predominantly 7.16-7.23 Å) show higher σ(1) affinities than their trans-configured counterparts (distance 1 is predominantly 5.88-6.26 Å).