3. Results and Discussions
3.1 QSAR of SBT
In order to quantitatively understand the dependence of
biological activities on a substituent at phenyl of SBT
and SBO, correlation studies were employed to
representative compounds listed in Tables 1-4 according to
Hansch-Fujita's method with stepwise regression analysis, leading
to eqns. (1)-(4), respectively. Both pKa values, the logs
of the reciprocals of Ka, and logVmax values were
used as OA-agonist activity index as the relatively low active
compounds were tested only the Vmax bioassay. For the QSAR
analysis, physicochemical and structural descriptors, including (total hydrophobic character), m(electronic effect sigma
meta), MR(molar refraction), Es(steric ), Esm(steric
meta), and (Esm)2 were investigated and
found to correlate with pKa and logVmax. The use of
other parameters [e.g., Taft's * and Es[11], the Hancock steric parameter Esc
[12],
Swain-Lupton-Hansch field and resonance effect constants F and R [13], STERIMOL L,
B1, and B5 [14],
Charton's electronic inductive and resonance constants I and R [15], and electronic inductive constant I by Taft and Lewis [16] instead of , m, MR, Es, Esm, and (Esm)2
or the addition of other parameters to eqns. (1)-(4) did not
improve the correlation.
logVmax=1.414(±0.013) + 0.663(±0.125)m + 0.118(±0.036)Esm
................ (1)
where n=17, r=0.8555, s=0.0475, and F=19.113.
According to eqn. (1), the electronic nature of a substituent was
the most important followed by the steric effect for the
OA-agonist activity of SBT against P. americana.
The positive m and Esm
terms mean that the more electron-withdrawing and the less bulky
the substituent at m-position, the greater the activity.
3,5-Cl2 derivative 17 had the highest Vmax,
followed by 3-F- (7) and 2-Me- (5) derivatives for
stimulating adenylate cyclase prepared from thoracic nerve cords
of P. americana (Table 1). Introduction of a Br, Cl, F,
Me, or CF3 to the o-position of a potent
2-benzylamino-2-thiazoline (1) increased the Vmax
further, leading to 2-5 respectively. Similarly,
the introduction of a F atom or CF3 group to the m-position
of 1 and of a Cl, Me, or MeO to the p-position of 1
increased Vmax, leading to 7-10,
respectively. Disubstituted SBTs 12-17 were
also more active than 1 in Vmax.
pKa = 3.720(±0.661) - 1.270(±0.270)logVmax +
0.343(±0.133)Esm + 0.266(±0.064)(Esm)2
.............. (2)
where n=18, r=0.9134, s=0.0453, and F=23.489.
The correlation of calculated pKa from eqn. (2) and
observed value from bioassay was examined and shown in Chart 1.
According to eqn. (2), the negative logVmax term means
that a proper smaller Vmax value increase the distribution
of pKa. This may be an interesting self-contradiction
between Vmax and pKa in evaluating the activity of
adenylate cyclase of P. americana for SBTs. The
positive Esm and (Esm)2 terms
indicate that there should be a minimum value for Esm.
Generally speaking, effects of m-substituted groups on the
activity in terms of both Vmax and pKa are more
significant than those caused by o,p-substituted
ones (Chart 1.). From another point of view, the activity in
terms of Vmax does not necessarily correlate with that in
terms of Ka in SBTs. 3-CF3 derivative 8
had the highest potency, followed by 3-Cl,4-F- (21) and
2-Br- (2) derivatives in terms of Ka for
stimulating adenylate cyclase prepared from thoracic nerve cords
of P. americana (Table 2). Introduction of a Br or CF3
to the o-position of a potent 2-benzylamino-2-thiazoline (1)
increased the potency, leading to 2 or 6,
respectively. Similarly, the introduction of a CF3
group or Cl atom to the m-position of 1 and of a
MeO or F to the p-position of 1 increased the
potency, leading to 8, 18, 11, and 19,
respectively. Disubstituted SBTs were also more active in Ka
than 1 except 2,5-F2- (16) and 3,5-F2-SBT
(23). The difference of substituents at phenyl of SBT
compounds in Vmax and pKa seems to be less
significant than that of 2-(arylimino)thiazolidines (AIT) [7]. The above
data suggest that phenyl ring substitution requirements for SBT
and AIT derivatives active as octopaminergic agonists
differ substantially from each other.
Chart 1. Observed pKa vs Calculated data from eqn. (2):
QSAR of SBT in term of pKa
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