| Summary: |
The invention
|
γ-Aminobutyric
two ionotropic receptors
(GABA-A and GABA-C), which are ligand-gated ion channels a metabotropic receptor (GABA-B), which is a member
of the class C family of G-protein-coupled receptors (GPCRs)
|
| The GABA-B |
| The GABA-B |
| The above data
show that the GABA-B receptor is a viable therapeutic target, but
its stimulation can be accompanied by severe side effects. Therefore,
researchers were inspired to identify and develop alternatives to
the classic orthosteric agonists to harness the benefits of the GABA-B
receptor activation without causing the undesired severe side effects
and drug tolerance. |
| The invention in this
patent application describes the use of positive allosteric modulators
(PAMs) of the GABA-B receptor as a better alternative to retain the
benefits of GABA-B stimulation while potentially eliminating or minimizing
the adverse effects of classic orthosteric agonists. PAMs can alter
the receptor conformation and enhance the activity of the endogenous
orthosteric agonist, either by increasing the affinity or the efficacy
of the orthosteric ligand at the receptor. |
| A single receptor may possess multiple, discrete allosteric sites,
each is functionally and topographically distinct with a unique subset
of ligands. PAMs do not have activities of their own, but they exert
their effects by binding to these allosteric sites, which are located
at a distance from the orthosteric site of the receptor. When PAMs
bind to the allosteric sites, they can alter the receptor conformation
and enhance the activity of the endogenous orthosteric agonist, either
by increasing the affinity or the efficacy of the orthosteric ligand
at the receptor. PAMs pharmacological profile is spatially and temporally
controlled by the normal physiological interaction between the endogenous
ligand and its receptor. They rely on endogenous agonist concentrations
for activity, and hence, they are thought to represent a safer and
more subtle means of receptor regulation to promote fine-tuning of
the GABA signal in a physiologically relevant manner. The hypothesis
is that GABA-B receptor allosteric modulators, and possibly allosteric
agonists, will be effective therapeutic agents while minimizing the
side effects caused by typical agonist activation of the orthosteric
GABA-B site. Another important finding is that GABA-B PAMs do not
cause receptor desensitization, so the clinical tolerance and side
effects related to receptor desensitization such as those observed
with baclofen are unlikely to occur. Finally, the majority of tested
GABA-B PAMs have shown excellent efficacies and greatly enhanced brain
penetrance compared to baclofen in preliminary studies with minimum
or no side effects. |
| Therefore, it is important
to identify new GABA-B PAMs, such as the compounds described in this
patent application, capable of stimulating the GABA-B receptor without
the baclofen-like side effects, which may potentially treat many disorders
mediated by this receptor. |
| Important
Compound Classes: |
 |
| Key Structures: |
The inventors described the structures and synthesis procedures for
137 examples of formula (I)
|
| Biological Assay: |
[35S] GTPγS {Guanosine 5′-O-[gamma-thio]triphosphate}
Binding Assay |
| Biological Data: |
The biological data obtained by testing the above
representative examples in the [35S] GTPγS binding
assay are listed in the following table:
|
| Recent Review Articles: |
Brown K. M.; Roy K. K.; Hockerman G. H.; Doerksen R. J.; Colby D. A.. J. Med.
Chem. 2015, 58 ( (16), ), 6336–47. |
| |
Filip M.; Frankowska M.; Sadakierska-Chudy A.; Suder A.; Szumiec L.; Mierzejewski P.; Bienkowski P.; Przegalinski E.; Cryan J. F.. Neuropharmacol. 2015, 88, 36–47. |
| |
Benarroch E. E.Neurology 2012, 78 ( (8), ), 578–584. |
| |
Nambu A.Exp. Neurol. 2012, 233 ( (1), ), 121–122. |
