SYNTHESIS AND KAPPA-BINDING-AFFINITY OF O)PHENYL]-1,2,3,4-TETRAHYDROISOQUINOLIN-3(2H)-ONES

Diastereomeric forms of )phenyl]-1,2,3,4-tetrahydroisoquinoline-3(2h)- ones 3a and its chloro analog 3c were synthesized. Compounds 3a,c are related to the kappa-selective opiate ICI 199441 1 by linking the benz ylic CH2 to the ortho position of the phenyl in 1. Compared with morph ine, these compounds had lost in kappa and mu affinities; only cis-3a showed a modest kappa affinity. chlorphenyl)acetyl]-1,2,3,4-tetrahydro isoquinoline 2, which is also a cyclic congener of 1, was reported to display high kappa and mu affinity, and so a conformational study was undertaken on 1, 2 and 3a. This showed that, while active 2 extensivel y superposed on 1, 3a assumes another geometry which does not allow a fit with the pharmacophoric moieties of 1 and 2.