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E u r o S c i C o n C o n f e r e n c e o n
Chemistry
2018
Chemistry 2018
Journal of Organic & Inorganic Chemistry
ISSN 2472-1123
F e b r u a r y 1 9 - 2 0 , 2 0 1 8
P a r i s , F r a n c e
Page 48
W ith respect to the mechanistic membrane interaction of drugs, there
are two critical subjects: whether drug stereoisomers interact with
membranes stereospecifically and whether they are effective in modifying
membrane physicochemical properties at clinically relevant concentrations.
We studied the comparative potencies of selected stereoisomers to interact
with liposomal membranes at concentrations to exhibit beneficial and adverse
action. Unilamellar vesicles were prepared with phospholipids and cholesterol
to mimic the lipid compositions of cardiomyocyte and neuronal membranes.
Stereoisomers of local anesthetic bupivacaine, β-adrenergic antagonist
propranolol and anti-inflammatory ibuprofen were subjected at 5-200 µM to
the reaction with biomimetic membranes and their membrane interactivities
were determined by measuring fluorescence polarization. Bupivacaine
stereoisomers interacted with 40 mol% cholesterol-containing cardiomyocyte-
mimetic membranes to induce a significant increase in membrane fluidity
at ~50 µM. Their membrane interactions showed the relative potency being
R(+)-bupivacaine>rac-bupivacaine>S(-)-bupivacaine, which correlated to
that of their cardiotoxicity. Such a stereostructure-dependent difference
became greater with lowering drug concentrations. Bupivacaine is considered
to localize at lipid-lipid and lipid-protein interfaces within cardiomyocyte
membranes, affecting the lipid environment surrounding membrane-
embedded sodium channels in a stereospecific manner. Both propranolol and
ibuprofen stereoisomers also interacted at clinically relevant concentrations
with neuro-mimetic membranes to change their fluidity with the relative
potency being R(+)-propranolol>rac-propranolol>S (‒)-propranolol and being
S(+)-ibuprofen>rac-ibuprofen>R(‒)-ibuprofen. The rank orders of membrane
interactivity of all the tested drug stereoisomers agreed with those of their
pharmacological and clinical effects. The opposite configuration allows
molecules to interact with membrane chiral cholesterol enantioselectively and
the specific β configuration of cholesterol’s 3-hydroxyl group appears to be
responsible for such selectivity. The stereospecific membrane interactivity
has implications for medicinal chemistry as a methodological index for drug
design to discriminate more active or toxic stereoisomers from less active or
toxic ones.
Biography
H Tsuchiya received his PhD based on a clinical chemistry
thesis from Gifu Pharmaceutical University. He served as a
research investigator at National Center for Nervous, Mental
and Muscular Disorders and University of Pennsylvania Monell
Chemical Senses Center. He is presently a chief professor of
Asahi University School of Dentistry. His current research in-
terests are related to medicinal chemistry of anesthetics and
phytochemicals. He has published more than 200 papers in
international journals.
Stereospecific membrane interactions of drug stereoisomers at
clinically relevant concentrations
H Tsuchiya1 and M Mizogami 2
1Asahi University, Japan
2University of Fukui, Japan
H Tsuchiya, J Org Inorg Chem 2018, Volume: 4
DOI: 10.21767/2472-1123-C1-003