6,7-Dimethoxytetrahydroisoquinoline is widely used as basic moiety in σ2 receptor ligands, in order to provide σ2versus σ1 selectivity. This same moiety is also widely exploited in modulators of P-glycoprotein (P-gp) efflux pump, so that mixed σ2/P-gp agents are often obtained. Deconstruction of 6,7-dimethoxytetrahydroisoquinoline moiety present in the potent mixed σ2/P-gp agent 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3,4-tetrahydroisoquinoline (1) could lead to the separation of σ2 affinity from P-gp activity. Therefore, phenethylamino-, benzylamino- and indanamine series were obtained. The NH group was also methylated in the N-phenethylamino series, and ethylated in the benzylamino series, to better match 6,7-dimethoxytetrahydroisoquinoline. The σ2 affinity drastically decreased with the increase of conformational freedom, whereas alkylation of the NH-group was beneficial for σ2 receptor interaction. By contrast, deconstruction of 6,7-dimethoxytetrahydroisoquinoline slightly reduced P-gp activity, with dimethoxy-substituted derivatives displaying potent P-gp interaction. Therefore, 'ring-opened' 6,7-dimethoxytetrahydroisoquinoline derivatives represent a promising strategy to obtain P-gp selective agents devoid of σ2 receptor affinity.