ethyl-N-propargyl-3-(4-phenoxy)phenoxypropylamine, an analogue of the
MAO-A-selective irreversible inhibitor clorgyline in which the 2,4-dic
hloro-substitution in clorgyline was replaced by a 2-H atom and a 4-ph
enoxy group, has been synthesised and assessed as an inhibitor of mono
amine oxidase (MAO). This compound proved to be a time-dependent irrev
ersible inhibitor of both MAO-A and -B. However, unlike clorgyline, it
was selective towards MAO-B, both in its initial, non-covalent, bindi
ng to the enzyme and as an irreversible inhibitor. In order to assess
the influence of side-chain length on inhibitory potency, analogues we
re synthesised in which the side-chain was reduced to 2 CH2 units meth
yl-N-propargyl-2-(4-phenoxy)phenoxyethylamine) or increased to 4 CH2 u
nits ethyl-N-propargyl-4-(4-phenoxy)phenoxybutylamine). Both these com
pounds were also time-dependent irreversible inhibitors with selectivi
ty towards MAO-B. In the case of the initial, non-covalent, inhibition
all these compounds were competitive inhibitors of MAO-A, with respec
t to the amine substrate, and the affinity for inhibitor binding incre
ased with carbon chain length. In contrast the compounds were all mixe
d inhibitors of MAO-B. The competitive element of this inhibition (mea
sured by K-is) was similar for the 2 and 3 carbon-chain compounds but
decreased markedly when the chain-length was increased to 4 carbons. T
he uncompetitive inhibition (measured by K-ii) decreased as the carbon
chain-length was increased from 2 to 3, but there was no significant
further change when the length was increased to 4 carbons. The time-de
pendent irreversible inhibition (measured as the IC50 values after 60
min enzyme-inhibitor preincubation) showed that the potency towards MA
O-A increased when the side-chain length was increased from 2 to 3 car
bons but that there was no significant difference between the 3 and 4
carbon-chain compounds. In the case of MAO-B inhibition, the 2 and 3 c
arbon-chain compounds had similar inhibitory potencies but this increa
sed substantially when the chain length was increased to 4 carbons. Th
e significance of the inhibitory behaviour of these compounds is discu
ssed in terms of the structure-activity relationships of mechanism-bas
ed irreversible MAO inhibitors.