AMINOPHOSPHINIC INHIBITORS AS TRANSITION-STATE ANALOGS OF ENKEPHALIN-DEGRADING ENZYMES - A CLASS OF CENTRAL ANALGESICS

Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zi nc metallopeptidases involved in the inactivation of the opioid peptid es enkephalins, produces potent physiological analgesic responses, wit hout major side-effects, in all animal models of pain in which morphin e is active. Dual inhibitors of both enzymes could fill the gap betwee n opioid analgesics and antalgics, Until now, attempts to find a compo und with high affinity both for neutral endopeptidase and aminopeptida se N have failed, We report here the design of dual competitive inhibi tors of both enzymes with K-1 values in the nanomolar range. These hav e been obtained by selecting R-1, R-2, and R-3 determinants in aminoph osphinic-containing inhibitors: NH2-CH(R-1)P(O)-(OH)CH2-CH(R-2) CONH-C H(R-3) COOH, for optimal recognition of the two enkephalin inactivatin g enzymes, whose active site peculiarities, determined by site-directe d mutagenesis, have been taken into account. The best inhibitors were 10x more potent than described dual inhibitors in alleviating acute an d inflammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effec ts.