Synthesis of C-2 substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines: binding studies on opioid receptors

Abstract The racemic C-2 substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines 8a–k were prepared in three steps from the readily available 2-cyano-1,2,5,6-tetrahydropyridines 4a–c . This involved alkylation of the anion of 4a–c with the appropriate alkyl halide, displacement of the cyano group in 5 or 6 by reaction with a Grignard reagent and cyclization under Grewe conditions (HBr, reflux). The equilibrium binding affinities of compounds 8a–k for the μ, δ and κ opioid receptor types were determined. Compounds 8c, 8e, 8j and 8k bearing a phenyl or olefinic substituent at C-2 display high κ receptor binding affinities demonstrating that the presence of a substituent at this position is important for κ receptor binding. The insensitivity of the binding of compounds 8j and 8k to sodium ions and guanine nucleotides at both μ and κ sites suggests that these 2-substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines could behave as partial agonists or antagonists. The binding of the molecule 8e to μ and κ sites was inhibited in the presence of these allosteric effectors, whereas N-methyl-2-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine 8c appears to display the same κ-agonist / μ-antagonist pharmacological profile as bremazocine 2 .