Novel Inhibitors of Enkephalin-Degrading Enzymes IV: Structure-Activity Relationships within the Penicillins as Enkephalinase Inhibitors

S. J. Livingston Welsh School of Pharmacy, U.W.C.C., P.O. Box 13, Cardiff, CFl 3XF, UK

H. J. Smith Welsh School of Pharmacy, U.W.C.C., P.O. Box 13, Cardiff, CFl 3XF, UK

R. D. E. Sewell Welsh School of Pharmacy, U.W.C.C., P.O. Box 13, Cardiff, CFl 3XF, UK

S. Ahmed Welsh School of Pharmacy, U.W.C.C., P.O. Box 13, Cardiff, CFl 3XF, UK

Abstract

A range of penicillins have been examined as competitive reversible inhibitors of enkephalinase (neutral endopeptidase; EC 3.4.24.11). Carfecillin (K_i = 0.18μM) was the most potent inhibitor in the series, whereas cloxacillin (27.5 μM), ampicillin (41.0 μM), nafcillin (58.7 μM) and carbenicillin (158 μM) had moderate potency and benzyl penicillin (885 μM), mezlocillin (473μM) and azlocillin (556 μM) were weak inhibitors. Structure-activity relationships within the series have been rationalised from a consideration of molecular graphics analysis of the match between receptor binding groups with thiorphan as well as log P values.

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Novel Inhibitors of Enkephalin-Degrading Enzymes IV: Structure-Activity Relationships within the Penicillins as Enkephalinase Inhibitors

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Novel Inhibitors of Enkephalin-Degrading Enzymes IV: Structure-Activity Relationships within the Penicillins as Enkephalinase Inhibitors

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