Inhibitors of the enkephalin degrading enzymes. Modulation of activity of hydroxamate containing compounds by modifications of the C-terminal residue.
To further characterize the S'2 subsite of both the neutral endopeptidase (EC 3.4.24.11, NEP) and aminopeptidase N (EC 3.4.11.2, APN), two enzymes physiologically involved in enkephalin metabolism, a new series of hydroxamate inhibitors containing a cyclic amino acid as the P'2 component were synthesized. These amino acids differ by the size of the cycle, the relative position of the functional groups, and their absolute configuration. Highly efficient inhibitors of NEP were obtained whatever the modification on the P'2 component, while for APN inhibition, a cyclic beta-amino acid was preferred. The most active inhibitors contained a trans cyclopentyl beta-amino acid and a cis or a trans cyclohexyl beta-amino acid. When injected intracerebroventricularly in mice, these two latter compounds elicited potent antinociceptive responses on both the jump latency and the fore paw lick times.
Xie
J
J
Department of Organic Chemistry, U 266 INSERM, UA 498 CNRS, Paris, France.
Soleilhac
J M
JM
Renwart
N
N
Peyroux
J
J
Roques
B P
BP
Fournié-Zaluski
M C
MC
D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D018826:CD13 Antigens; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011817:Rabbits
D000596:Amino Acids; D000700:Analgesics; D003510:Cyclohexanes; D003517:Cyclopentanes; D006877:Hydroxamic Acids; D000626:Aminopeptidases; D018826:CD13 Antigens; D015260:Neprilysin