Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome p450 activities
S. Koul et al., Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome p450 activities, BIO MED CH, 8(1), 2000, pp. 251-268
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.