| Abstract
| - The development of dual inhibitors of the two zinc metallopeptidases, neprilysin (neutralendopeptidase) and aminopeptidase N involved in the inactivation of the opioid peptides,enkephalins, represents an attractive physiological approach in the search for new analgesicsdevoid of the major drawbacks of morphine. Phosphinic compounds, corresponding to the generalformula H3N+-CH(R1)-P(O)(OH)-CH2-CH(R2)-CONH-CH(R3)-COO-, able to act as transition-state analogues and to fit the S1, S1‘, and S2‘ subsites of both enzymes were designed. Selectionof the R1, R2, and R3 residues for optimal recognition of these enzymes led to the first dualcompetitive inhibitors with Ki values in the nanomolar range for neprilysin and aminopeptidaseN. These compounds induce potent analgesic responses after intracerebroventricular orintravenous administrations in mice (hot plate test), and several of them were shown to be, atleast, 10 times more potent than the previously described dual inhibitors.
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