INHIBITION OF MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B ACTIVITIES BY IMIDAZOL(INE) GUANIDINE DRUGS, NATURE OF THE INTERACTION AND DISTINCTION FROM I-2-IMIDAZOLINE RECEPTORS IN RAT-LIVER/
A. Ozaita et al., INHIBITION OF MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B ACTIVITIES BY IMIDAZOL(INE) GUANIDINE DRUGS, NATURE OF THE INTERACTION AND DISTINCTION FROM I-2-IMIDAZOLINE RECEPTORS IN RAT-LIVER/, British Journal of Pharmacology, 121(5), 1997, pp. 901-912
1 I-2-Imidazoline sites ([H-3]-idazoxan binding) have been identified
on monoamine oxidase (MAO) and proposed to modulate the activity of th
e enzyme through an allosteric inhibitory mechanism (Tesson et al., 19
95). The main aim of this study was to assess the inhibitory effects a
nd nature of the inhibition of imidazol(ine)/guanidine drugs on rat li
ver MAO-A and MAO-B isoforms and to compare their inhibitory potencies
with their affinities for the sites labelled by [H-3]-clonidine in th
e same tissue. 2 Competition for [H-3]-clonidine binding in rat liver
mitochondrial fractions by imidazol(ine)/guanidine compounds revealed
that the pharmacological profile of the interaction (2-styryl-2-imidaz
oline, LSL 61112>idazoxan>2-benzofuranyl-2-imidazoline, 2-BFI = cirazo
line>guanabenz>oxymetazoline>>clonidine) was typical of that for I-2-s
ites. 3 Clonidine inhibited rat liver MAO-A and MAO-B activities with
very low potency (IC(50)s: 700 mu M and 6 mM, respectively) and displa
yed the typical pattern of competitive enzyme inhibition (Lineweaver-B
urk plots: increased K-m and unchanged V-max values). Other imidazol(i
ne)/guanidine drugs also were weak MAO inhibitors with the exception o
f guanabenz, 2-BFI and cirazoline on MAO-A (IC(50)s: 4-11 mu M) and 2-
benzofuranyl-2-imidazol (LSL 60101) on MAO-B (IC50: 16 mu M) Idazoxan
was a full inhibitor, although with rather low potency, on both MAO-A
and MAO-B isoenzymes (IC(50)s: 280 mu M and 624 mu M, respectively). K
inetic analyses of MAO-A inhibition by these drugs revealed that the i
nteractions were competitive. For the same drugs acting on MAO-B the i
nteractions were of the mixed type inhibition (increased K-m and decre
ased V-max values), although the greater inhibitory effects on the app
arent value of V-max/K-m than on the V-max value indicated that the co
mpetitive element of the MAO-B inhibition predominated. 4 Competition
for [H-3]-Ro 41-1049 binding to MAO-A or [H-3]-Ro 19-6327 binding to M
AO-B in rat liver mitochondrial fractions by imidazol(ine)/guanidine c
ompounds revealed that the drug inhibition constants (K-i values) were
similar to the IC50 values displayed for the inhibition of MAO-A or M
AO-B activities. In fact, very good correlations were obtained when th
e affinities of drugs at MAO-A or MAO-B catalytic sites were correlate
d with their potencies in inhibiting MAO-A (r = 0.92) or MAO-B (r = 0.
99) activity. This further suggested a direct drug interaction with th
e catalytic sites of MAO-A and MAO-B isoforms. 5 No significant correl
ations were found when the potencies of imidazol(ine)/guanidine drugs
at the high affinity site (pK(iH), nanomolar range) or the low-affinit
y site (pK(iL), micromolar range) of I-2-imidazoline receptors labelle
d with [H-3]-clonidine were correlated with the pIC(50) values of the
same drugs for inhibition of MAO-A or MAO-B activity. These discrepanc
ies indicated that I-2-imidazoline receptors are not directly related
to the site of action of these drugs on MAO activity in rat liver mito
chondrial fractions. 6 Although these studies cannot exclude the prese
nce of additional binding sites on MAO that do not affect the activity
of the enzyme, they would suggest that I-2-imidazoline receptors repr
esent molecular species that are distinct from MAO.