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.


Table1. QSAR of <b>SBT</b>(<i>V</i>max)

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.

Table 2.  QSAR  (<i>K</i>a) of <b>SBT</b>

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




Next page /Previous page /Table of Contents