Conclusions
In summary, the above studies demonstrate that SBTs and SBOs
with certain substituents can be potent agonists to OA receptors
associated with the activation of adenylate cyclase. And they
provide new information regarding the efficiency and potency of
oxazoline and thiazoline derivatives. QSAR and preliminary
modelling studies suggest that the enhanced potency of SBOs
and SBTs may be due to the potential electronic
interaction of the m-substituted benzyl ring with the
undefined pocket or residue at the receptor site. The steric
demands are also important especially of SBTs and
essential for the molecular recognition at the OA receptor site
as shown by both the QSAR and the molecular fitting models by the
SEAL technology. These important information may help to point
the way towards developing extremely potent and relatively
specific OA agonists which could be useful as insectistatics
rather than insecticidal agents with reduced toxicity for
vertebrates.
An important messsage from this study for those involved in the
design of bioactive molecules is that quantum chemistry and
molecualr modelling techniques might provide mechanistic insight
where structure variation is far beyond the reach of the classic
QSAR methods. In the meantime, the fact that conformational
flexibility and further similarity indics in this study for SBTs
and SBOs seem to deal well with the QSAR results suggests
more fruitful directions for analogue synthesis. And we believe
that such established computing systems as CAChe™ or other
packages may be offering interesting resourses of molecular
orbitals and other indices like similarity indice etc. to favour
the structure-activity relationship study, as it's reasonable and
reliable to translate chemical constitutions into numerical
values via topological methodologies. Such studies will hopefully
improve the understanding of octopaminergic agonist-receptor
interaction mechanisms, and may lead to the discovery of new
insectistatical agents which have improved potency and
effectiveness.
Acknowledgments
We thank Emeritus Prof. Toshio Fujita of Kyoto University and
Tanabe Pharmacology Co. Japan for donating the QSAR program. And
we are grateful to Prof. Takaaki Sonoda of Institute of Advanced
Material Study, Kyushu University, Japan for allowing us to use
the CAChe Groupserver IBM RS6000. We also want to thank
MicroSimulations Co. for providing evaluation project for
Powerit1.0 and related MicroSimulation software. This work was
supported in part by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, and Culture of Japan.
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