Asymmetric Synthesis and Enantiospecificity of Binding of 2‐(1,2,3,4‐Tetrahydro‐1‐isoquinolyl)‐ethanol Derivatives to μ and κ Receptors

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 CH 2 O and NaCNBH 3 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 K i value of 7.17 which is close to that of Morphine ( K i = 1.64). In an in vivo model, the Writhing Test, both compounds l ‐ 7d and l ‐ 7e displayed high analgetic activity.