Synthesis and κ binding affinity of 1-(pyrrolidin-1-ylmethyl)-2-(N-methyl)-4--1,2,3,4-tetrahydroisoquinolin-3(2H)-ones

Article abstract of DOI:10.1016/0223-5234(96)88263-8

Diastereomeric forms of 1-(pyrrolidin-1-ylmethyl)-2-(N-methyl)-4-<(3,4-dichloro)phenyl>-1,2,3,4-tetrahydroisoquinolin-3-(2H)-ones 3a and its chloro analog 3c were synthesized.Compounds 3a,c are related to the κ-selective opiate ICI 199441 1 by linking the benzylic CH2 to the ortho position of the phenyl in 1.Compared with morphine, these compounds had lost in κ and μ affinities; only cis-3a showed a modest κ affinity. 1-Pyrrolidin-1-ylmethyl-N-<2-(3,4-dichlorophenyl)acetyl>-1,2,3,4-tetrahydroisoquinoline 2, which is also a cyclic congener of 1, was reported to display high κ and μ affinity, and so a conformational study was undertaken on 1, 2 and 3a.This showed that while active 2 extensively superposed on 1, 3a assumes another geometry which does now allow a fit with the pharmacophoric moieties of 1 and 2. tetrahydroisoquinolin-3(2H)-one / κ-opiate receptor / rigid congener