Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome p450 activities

Inhibitors of drug metabolism have important implications in pharmaco-toxic ology and agriculture. We have reported earlier that piperine, a major alka loid of black and long peppers inhibits both constitutive and inducible cyt ochrome P450 (CYP)dependent drug metabolising enzymes. In the present study , an attempt has been made to prepare several novel synthetic analogues so as to relate various modifications in the parent molecule to the inhibition of CYP activities. Two types of mono-oxygenase reactions arylhydrocarbon h ydroxylase (AHH) and 7-methoxycoumarin-O-demethylase (MOCD) have been studi ed. Inhibition studies were investigated in rat microsomal fraction prepare d from untreated, 3MC- and PB- treated rat liver in vitro. Modifications we re introduced into the piperine molecule: (i) in the phenyl nucleus, (ii) i n the side chain and (iii) in the basic moiety. Thus, 38 compounds have bee n subjected to such studies, and simultaneously an attempt has also been ma de to arrive at the structure-activity relationship of synthetic analogues. In general, most of the inhibitory potential of the parent molecule is los t with modification in either of the three components of piperine. Saturati on of the side chain resulted in significantly enhanced inhibition of CYP w hile modifications in the phenyl and basic moieties in few analogues offere d maximal selectivity in inhibiting either constitutive or inducible CYP ac tivities. Thus Few novel analogues as CYP inactivators have been synthesize d which may have important consequences in pharmacokinetics and bioavailabi lity of drugs. (C) 2000 Elsevier Science Ltd. All rights reserved.