Biomedical Engineering Reference
In-Depth Information
2.1.2
Lipophilicity of TA
Despite the presence of polar moieties including, e.g. tertiary amine, ester-,
hydroxyl- and epoxy-groups, non-protonated uncharged TTA are quite lipophilic.
Lipophilicity is mainly caused by the heterocyclic tropane structure and aromatic
(substituted) phenyl rings (Fig.
1
).
The octanol-water partition coefficient (
K
OW
), characterizing distribution of a
non-ionized compound between an octanol (o) and an immiscible aqueous (w)
layer, may function as a measure of lipophilicity, that is often listed as its logarith-
mic value (log
P
). Therefore, log
P
may be used as a predictor of extractability in
LLE. Table
1
presents log
P
values of TA calculated by the
Molinspiration
software
[
25
] using SMILES notation for chemical structures. The SMILES concept is
addressed in the next section [
26
]. Conformity of calculated (calc.) and experimen-
tal (exp.) log
P
values is satisfying, as exemplarily shown for atropine (1.83 exp.
[
27
]; 1.77 calc.) and scopolamine (0.98 exp. [
22
] ; 1.05 calc.).
The most lipophilic TA are benztropine (log
P
4.27) (Fig.
1
) and bemesetron (log
P
4.19) (Fig.
1
), possessing either two non-substituted phenyl rings (benztropine) or
one dichlorinated phenyl ring (bemesetron). In contrast, the most hydrophilic com-
pounds are QTA due to the presence of the permanent positive charge. However, as
determination of
K
ow
requires non-ionized molecular species, calculated log
P
val-
ues might be inaccurate for QTA but surely demonstrate the weak tendency of these
substances to be transferred into an organic non-polar phase (Table
1
).
Consideration of log
P
can also be useful to assess extractability by solid-phase
extraction (SPE) using reversed-phase (RP) material as well as retention properties
on HPLC columns of such material [
28
] .
2.1.3
SMILES Notation
SMILES is the abbreviation for simplified molecular input line entry system. This
system allows to describe two-dimensional chemical strcutures in a simple linear
text form as shown for diverse TA in Table
1
. To give an example, atropine (Fig.
1
)
is described by the sequence: CN1C3CCC1CC(OC(=O)C(CO)c2ccccc2)C3, which
was directly generated by the
Molinspiration
software after presetting the chemical
structure. As obvious hydrogen bonds are not symbolized. The pattern (OC(=O)
C(CO) for example represents the ester moiety (OC(=O)), that is bound to a meth-
ylene carbon atom, C, that carries the hydroxymethylene group (CO) (Fig.
1
). The
phenyl ring is coded by c2ccccc2, describing six aromatic carbon atoms (six times
lower case C) spanning a second (2) cyclic structure in the molecule (besides the
tropane bicyclus). For more details on construction rules of the SMILES code the
reader is referred to an online tutorial offered by, e.g. the U.S. Environmental
Protection Agency (EPA) [
26
] .
SMILES provides an-easy-to-handle-format useful for entries in any software
application. Therefore, based on the SMILES code p
K
b
and log
P
values can be
predicted beneath other chemical and biological properties (Table
1
).
