SEARCH

SEARCH BY CITATION

Keywords:

  • opioid analgesics; biological enantioselectivity; tetrahydroisoquinolines; 1,3-amino alcohols; asymmetric synthesis

Abstract

A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a—e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a—c and ent-5a—c, which were accessible by employing 3b and ent-3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a—c and ent-5a—c the amido alcohols l-6a—c, u-6a—c, ent-l-6a—c and ent-u-6a—c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l-7a—c, u-7a—c, ent-l-7a—c and ent-u-7a—c and upon reductive methylation of l-7b—c, u-7b—c, ent-l-7b—c and ent-u-7b—c with CH2O and NaCNBH3 the tertiary amino alcohols l-7d—e, u-7d—e, ent-l-7d—e and ent-u-7d—e were obtained.

The binding affinities of the final compounds l-7a—e, u-7a—e, ent-l-7a—e and ent-u-7a—e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a—c the affinity at the μ receptor followed the stereochemical order l-7 > ent-l-7 > ent-u-7 > u-7 whereas for the tertiary amino alcohols the order l-7 > u-7 > ent-l-7 > ent-u-7 was found. The stereoisomers l-7d and l-7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l-7d and l-7e displayed high analgetic activity.