604
Chirality in Biology
F
3
C
O
CHF
2
Cl
H
N
N
H
O
O
OC
HN
C
O
NH
CO
C
C
2
H
5
H
OC
N
C
NH
CO
C
C
2
H
5
H
S
Na
+
(a)
(b)
(c)
(d)
Fig. 16
Chiral anesthetic
agents.
(
a
)
=
(
S
)
-isoflurane;
(
b
)
=
(
R
)
-etomidate;
(
c
)
=
(
S
)
-5-ethyl-5(1,3-
dimethylbutyryl)-barbital;
(
d
)
=
(
S
)
-thiopental.
It is about fve times as active as the (
S
)
-
(
) Form. ±or the barbiturate compounds
used as anesthetics and hypnotics, many
agents show Case 3 pharmacodynamic ac-
tion; a depressant activity is observed in
the (
S
) Forms, while an excitatory activity is
associated with the (
R
) enantiomer. Thus,
For 5-ethyl-5(1,3-dimethylbutyryl)-barbital,
the (
S
)Form(±ig
.16c)isadepressantand
the (
R
) Form is a convulsant; the racemate
is also a convulsant and is not suitable
For clinical use. In the clinically useFul
thiopental sodium, studies in mice and hu-
man volunteers indicate greater potency
For the (
S
) Form (±ig. 16d). However, in
animals it yields a lower therapeutic ratio.
It has a shorter terminal halF-liFe being
cleared and metabolizes more rapidly.
Drug enantiomers show many phar-
macokinetic diFFerences such as rates oF
adsorption and/or transport to receptor
sites and in rates oF metabolism to vari-
ous end products. ±or more details, the
specialist literature should be consulted.
±urther complications such as diFFerences
in animals versus humans and diFFerences
depending on sex and genetic makeup
can arise.
One consequence oF the interest in
chiral drugs has been a lot oF work
oF a chemical nature – For instance, the
June 10, 2002 issue oF
Chemical
and
Engineering News
Features ‘‘Chiral Chem-
istry’’
as
a
cover
story.
Syntheses
oF
chiral materials have been devised us-
ing
asymmetric
chemical
catalysis,
or
enzymes, or microbial systems. More-
over, many chromatographic techniques
have been developed For chiral separations,
both analytically and For preparative pur-
poses. This work is beyond the scope oF
this review.
4
Chiral Recognition
Enantiospecifc physiological eFFects imply
that enzymes or drug receptors achieve
‘‘chiral
recognition’’.
Much
work
has
Focused on the Easson–Stedman three-
point attachment model, proposed initially
to
account For
drug
enantioselectivity.
Given three specifc binding sites in a
plane, only one enantiomer can bind
to the surFace (±ig. 17). However, it is
now clear that in the absence oF specifc
constraints, the minimal requirement For
chiral recognition is interaction between
eight
atomic
centers,
involving
Four
diFFerent
nonplanar
centers
on
each
interacting molecule. The interactions may
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