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

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 mu and kappa 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 mu and the kappa receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the mu than at the kappa receptor. For the secondary amino alcohols 7a-c the affinity at the mu 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.

Stereoselective 1-arylation of isoquinolines via chiral N-acylisoquinolinium salts

“…1 2-Acyl-1-arylisoquinolines were used as precursors for such ligands. 2,3 1-Aryldihydroisoquinolines were used as precursors in the synthesis of fused isoquinolines. 4 Certain 2-acyl-1-aryl-1,2,3,4-tetrahydroisoquinolines are potent AMPA receptor antagonists.…”

C1‐Substituted N‐Alkyl Tetrahydroisoquinoline Derivatives through V‐Catalyzed Oxidative Coupling

“…We identified methopholine [11] 21, an opioid analgesic, as a potential target, which could be accessed through the hydrogenation of coupling product 15. Treatment of 15 with Pd(OH) 2 and hydrogen provided 21 in near quantitative yield (Scheme 5).…”

NMDA-NR2B subtype selectivity of stereoisomeric 2-(1,2,3,4-tetrahydro-1-isoquinolyl)ethanol derivatives

“…13,14 We discovered that the potency of the amino alcohols 4a-d at the l and j opioid receptors is strongly dependent on their configuration. Besides, within a set of isomers, the highest affinity has been always displayed by the same stereoisomer (1R,1 0 R)-4 (Table 1).…”