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Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7‐Substituted Coumarins
Author(s) -
Carotti Angelo,
Altomare Cosimo,
Catto Marco,
Gnerre Carmela,
Summo Luciana,
De Marco Agostino,
Rose Sarah,
Jenner Peter,
Testa Bernard
Publication year - 2006
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200690017
Subject(s) - lipophilicity , chemistry , coumarin , in vivo , monoamine oxidase b , monoamine oxidase , stereochemistry , ex vivo , enzyme , in vitro , biochemistry , organic chemistry , microbiology and biotechnology , biology
A series of coumarin derivatives ( 1 – 22 ), bearing at the 7‐position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase‐A and ‐B (MAO‐A and ‐B) inhibitory activities. Most of the compounds acted preferentially as MAO‐B inhibitors, with IC 50 values in the micromolar to low‐nanomolar range. A structure–activity‐relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO‐B inhibition potency of 7‐substituted coumarins, as shown by a linear correlation ( n =20, r 2 =0.72) between p IC 50 and calculated log P values. The stability of ester‐containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase‐catalyzed hydrolysis. Two compounds ( 14 and 22 ) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most‐potent and ‐selective MAO‐B inhibitor 22 (=7‐[(3,4‐difluorobenzyl)oxy]‐3,4‐dimethyl‐1‐benzopyran‐2(2 H )‐one) within the examined series significantly inhibited (>60%) ex vivo rat‐liver and striatal MAO‐B activities 1 h after intraperitoneal administration of high doses (100 and 300 μmol kg −1 ), revealing its ability to cross the blood–brain barrier. At the same doses, liver and striatum MAO‐A was less inhibited in vivo , somehow reflecting MAO‐B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14 , bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO‐B activity in vivo , and none on striatal MAO‐B, but, surprisingly, displayed inhibitory effects on MAO‐A in both peripheral and brain tissues.