Interaction mechanisms of imipramine and desipramine with enkephalin-degrading aminopeptidases in vitro

In the last few years, considerable evidence has appeared concerning the importance of the opioid systems in the action mechanism of some antidepressant drugs. This action mechanism could be mediated through the inhibition of the enzymes reponsible for enkephalin degradation. In this sense, imipramine treatment in vivo increases the enkephalin levels, and this effect is enhanced by inhibitors of enkephalin-degrading enzymes. The present work shows the effects in vitro of imipramine and its active metabolite desipramine on the activities of two membrane-bound enkephalin-degrading aminopeptidases present in rat brain. Imipramine and desipramine in vitro do not affect the aminopeptidase M activity, but they reversibly inhibits the aminoeptidase Mil. The enzyme kinetic analysis shows that this enzyme molecule has two different binding sites for each drug, which exert a mixed type enzyme inhibition. (C) 1997 Elsevier Science Inc.