(1S)-1-(Aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: Members of a novel class of very potent κ opioid analgesics

Article abstract of DOI:10.1021/jm00112a042

The synthesis and structure-activity relationship (SAR) of a novel class of κ opioid analgesics, 1-(amino-methyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N₂-C₁-C₉-N₁₀ pharmacophore torsional angle of approximately 60° was also found for this class of compounds by using X-ray and ¹H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of κ receptor selectivity was a feature of this novel class of antinociceptive agents (μ/κ ratio from 44 to 950 according to the nature of the basic moiety). A SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED₅₀ ca. 0.020 μM/kg sc) and κ ligands (K(i)(κ) ca. 0.20 nM) identified so far.