Syntheses of sterically constrained and diacylated peptidomimetic opioids

The opioid receptor system is characterized by at least three types of receptors (μ, δ, κ) and several receptor subtypes have been postulated. Receptor-specific agonists may provide analgesia without the deleterious side effects of the commonly administered μ-receptor agonists. In our laboratories, there is an ongoing effort to synthesize potent and δ-receptor selective peptide opioids. Peptidomimetics are designed, synthesized and incorporated into enkephalin analogs, and the resulting target compounds are subjected to biological and conformational analyses.; A new asymmetric synthesis of α-methyl-D-cysteine was accomplished. The incorporation of αMe-D-Cys into [αMe-D-Cys2, Cys5] enkephalin resulted in an active, but non-selective δ-receptor analog. The incorporation of αMe-D-Cys into [D-Cys2, αMe-D-Cys 5] resulted in a highly potent and δ-selective ligand.; Several β,β-dimethylated amino acids were synthesized using an asymmetric Strecker reaction. A new methodology to prepare α,α-dialkylated-β-lactams via Mannich-type reactions was successfully achieved. Different conditions were investigated to transform these β-lactams into the corresponding β,β-dialkylated aspartic acids and β,β-dialkylated diaminobutyric acids.; On the basis of results obtained for previously synthesized bridged-enkephalins, we undertook the parallel synthesis of novel diacyl-bridged enkephalin analogs (DABE). From the series of compounds synthesized, diacyl maloyl DABE exhibits the best δ-receptor selectivity.