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

Pub. Date : 2015 Jan 7

PMID : 25462276






5 Functional Relationships(s)
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1 Deconstruction of 6,7-dimethoxytetrahydroisoquinoline moiety present in the potent mixed sigma2/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 sigma2 affinity from P-gp activity. 6,7-dimethoxytetrahydroisoquinoline ATP binding cassette subfamily B member 1 Homo sapiens
2 Deconstruction of 6,7-dimethoxytetrahydroisoquinoline moiety present in the potent mixed sigma2/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 sigma2 affinity from P-gp activity. 6,7-dimethoxytetrahydroisoquinoline ATP binding cassette subfamily B member 1 Homo sapiens
3 By contrast, deconstruction of 6,7-dimethoxytetrahydroisoquinoline slightly reduced P-gp activity, with dimethoxy-substituted derivatives displaying potent P-gp interaction. 6,7-dimethoxytetrahydroisoquinoline ATP binding cassette subfamily B member 1 Homo sapiens
4 By contrast, deconstruction of 6,7-dimethoxytetrahydroisoquinoline slightly reduced P-gp activity, with dimethoxy-substituted derivatives displaying potent P-gp interaction. 6,7-dimethoxytetrahydroisoquinoline ATP binding cassette subfamily B member 1 Homo sapiens
5 Therefore, "ring-opened" 6,7-dimethoxytetrahydroisoquinoline derivatives represent a promising strategy to obtain P-gp selective agents devoid of sigma2 receptor affinity. 6,7-dimethoxytetrahydroisoquinoline ATP binding cassette subfamily B member 1 Homo sapiens