Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate Pglycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

6,7-Dimethoxytetrahydroisoquinoline is widely used as basic moiety in s2 receptor ligands, in order to provide s2 versus s1 selectivity. This same moiety is also widely exploited in modulators of P-glycoprotein (P-gp) efflux pump, so that mixed s2/P-gp agents are often obtained. Deconstruction of 6,7- dimethoxytetrahydroisoquinoline moiety present in the potent mixed s2/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 s2 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 s2 affinity drastically decreased with the increase of conformational freedom, whereas alkylation of the NH-group was beneficial for s2 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 s2 receptor affinity