Treatment of the commercially available 3-methoxyphenylacetonitrile (6) with sodium bis (trimethylsilyl)amide and subsequent cyclobisalkylation with α,ω-dibromo or dichloroalkanes in THF at 0 °C produces adducts 7a-d, which serve as precursors to the new conformationally constrained phenylalkylamides 5a-h. Compounds 5a-f are melatonin receptor agonists in the Xenopus laevis melanophore assay and their potency depends on both the size of the R group and the size and shape of the β-substituent. The fact that the cyclohexano-substituted analogs 5g and 5h are, regardless of the size of the R group, melatonin receptor antagonists, implies that the nature of the β-substituent constitutes a functional probe in the receptors dynamic agonist-antagonist conformational equilibrium.
Keywords: N-acyl 1-(3-methoxyphenyl)cycloalkanomethanamines, design, synthesis, melatoninergic activity
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