NEW ACHIEVEMENTS IN THE DEVELOPMENT AND STUDY OF THE MECHANISMS OF ACTION
OF THE LOW MOLECULAR WEIGHT AGONISTS OF RECEPTORS
OF THE THYROID-STIMULATING AND THE LUTEINIZING HORMONES
A.O. Shpakov
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg;
e-mail: alex_shpakov@list.ru
Pituitary glycoprotein hormones, luteinizing (LH) and thyroid-stimulating (TSH), exert their regulatory effects
on cells through the G protein-coupled receptors, specifically binding to their extracellular domain. There
is an alternative way of activation of LH and TSH receptors, when low molecular weight organic molecules
bind to an allosteric site of the receptors which is localized within their transmembrane channel. Low molecular
weight agonists have many advantages over glycoprotein hormones, among them a high efficiency not only in
the case of the parenteral but also in the oral administration, low immunogenicity, chemical stability, and a low
cost. Unlike pituitary glycoprotein hormones with the agonistic activity, low molecular weight compounds may
be either agonists or inverse agonists and neutral antagonists. Recently it was shown that low molecular weight
agonists of LH receptor are able to stimulate its mutant forms by restoring the processing of receptor in a cell,
and by increasing its sensitivity to LH, which is important for the treatment of reproductive dysfunctions caused
by mutations in the LH receptor. This review summarizes the recent achievements that are linked with the development
of low molecular weight regulators of TSH and LH receptors and the study of their mechanisms of action.
It also presents the author’ data concerning the creation of new low molecular weight agonists of LH receptor
based on the thienopyrimidine structure, which are effective both in vitro, and in vivo in different ways
of administration.
Key words:
allosteric site, luteinizing hormone, low molecular weight agonist, receptor, thienopyrimidine,
thyroid-stimulating hormone
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