GENEVA, SWITZERLAND--(Marketwire - November 28, 2011) -
Addex Pharmaceuticals /
Addex Scientists Discover Glucagon-like-peptide-1 (GLP-1) Induced
Interaction
Between GLP-1 and Gastric Inhibitory Peptide (GIP) Receptors
. Processed and transmitted by Thomson Reuters ONE.
The issuer is solely responsible for the content of this announcement.
The Addex Allosteric Modulator Platform Enabled Breakthrough Discovery,
Advancing the Understanding of GLP-1 Mediated GPCR Signaling
Addex Pharmaceuticals (SWISS: ADXN), a
leading biopharmaceutical company pioneering allosteric modulation-based
drug
discovery and development, announced today that its scientists have
demonstrated
that, in the presence of GLP-1, glucagon-like-peptide-1 receptor
(GLP1R) can
form a heterodimer receptor complex with gastric-inhibitory-peptide-
receptor
(GIPR). The discovery of this novel interaction between the two G-
protein-
coupled receptors (GPCR) has the potential to trigger the discovery of
novel
therapies for the treatment of diabetes. The findings were published
online in
the peer-reviewed journal Molecular Pharmacology (Lateral Allosterism
in the
Glucagon Receptor Family: GLP-1 Induces GPCR Heteromer Formation
[Schelshorn et
al., Molecular Pharmacology, Published online, doi:
10.1124/mol.111.074757]).
"GIPR and GLP1R are found together in pancreatic and nerve cells, and
their
roles in Type 2 diabetes make them important targets for drug
development.
Further research is needed to determine the pharmacological relevance of
such
heteromers but understanding their role may open the door to more
refined
therapies, particularly in metabolic disorders," explained Robert Lutjens,
head
of biology at Addex Pharmaceuticals and co-author of the publication.
"This
study demonstrates that Addex' allosteric modulation platform is a powerful
tool
for elucidating fundamental biological processes in addition to being the
most
sensitive method available for identifying allosteric modulators."
In the present study, the researchers at Addex used Bioluminescence
Resonance
Energy Transfer (BRET) techniques, calcium flux measurements, and
microscopy to
study receptor interactions within the glucagon receptor family of
GPCRs.
Through these techniques, a GLP-1-induced heteromer formation was
exclusively
observed in cells co-expressing GLP-1 with GIP receptors, but not with
other
receptors of the glucagon receptor subtypes. Furthermore, the
pharmacology of
this GLP-1-induced heteromeric receptor complex was found to be
affected in
presence of GIP. In addition, the heteromer's intracellular signaling
through
beta-arrestin or calcium second messenger was shown to be modified when
compared
to receptor homodimers, suggesting a form of allosteric regulation
between the
receptors.
"This research demonstrates how our pioneering allostery platform
technology is
able to observe specific interactions at the receptor level that have not
been
seen with conventional state-of-the-art techniques," noted Laurent
Galibert,
head of metabolic disease programs at Addex Pharmaceuticals. "An
orally
available small molecule targeting GLP1R would have a significant impact
on the
treatment of Type 2 diabetes. We now have the opportunity to
explore and
characterize this receptor further, paving the way for a better
understanding of
the signaling pathways implicated in diabetes and metabolism, which may
offer
novel therapeutic targets for allosteric modulation."
GLP-1 is an important metabolic hormone and a proven therapeutic
ligand for
treatment of diseases, such as Type II diabetes and obesity. Addex is
leading
the effort towards the development of orally available small molecule
GLP1R
activators, called positive allosteric modulators or PAM, which have
potential
to offer multiple advantages over marketed injectable peptide
therapeutics
targeting GLP1R.
Addex has previously disclosed that it achieved the first in vivo
preclinical
proof of concept demonstrating that an oral small molecule GLP1R PAM could
increase the release of insulin and improve glucose control in preclinical
diabetes models. Addex GLP1R PAMs are in lead generation phase for Type 2
diabetes and could become the first-in-class orally available small
molecule
therapeutic agents against this target.
Addex Pharmaceuticals (www.addexpharma.com) discovers and develops an
emerging
class of small molecule drugs, called allosteric modulators, which
have the
potential to be more specific and confer significant therapeutic advantages
over
conventional "orthosteric" small molecule or biological drugs. The Company
uses
its proprietary discovery platform to address receptors and other proteins
that
are recognized as attractive targets for modulation of important diseases
with
unmet medical needs. The Company's two lead products are being
investigated in
Phase IIa clinical testing: dipraglurant (ADX48621, an mGluR5
negative
allosteric modulator or NAM) is being developed by Addex to treat
Parkinson's
disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2
positive
allosteric modulator or PAM) is being developed by our partner
Janssen
Pharmaceuticals Inc. to treat schizophrenia. Addex also is advancing
several
preclinical programs including: GABA-BR PAM for pain, overactive
bladder and
other disorders; mGluR4 PAM for Parkinson's, anxiety and other diseases;
GLP1R
PAM for Type 2 diabetes; mGluR2 NAM for treating Alzheimer's
disease and
depression; and FSHR/LHR NAM for sex hormone dependent tumors &
reproductive
system disorders. In addition, Addex has discovery programs to
identify
allosteric modulators of: receptor tyrosine kinase (RTK) superfamily,
including
TrkB PAM for treating neurodegenerative diseases (e.g. Alzheimer's,
Parkinson's
and Huntington's diseases); and TNF receptor superfamily, including
TNFR1 NAM
for inflammation (e.g. rheumatoid arthritis) and other diseases.
Disclaimer: The foregoing release may contain forward-looking statements
that
can be identified by terminology such as "not approvable",
"continue",
"believes", "believe", "will", "remained open to exploring", "would",
"could",
or similar expressions, or by express or implied discussions regarding
Addex
Pharmaceuticals Ltd, its business, the potential approval of its
products by
regulatory authorities, or regarding potential future revenues from
such
products. Such forward-looking statements reflect the current views of
Addex
Pharmaceuticals Ltd regarding future events, future economic
performance or
prospects, and, by their very nature, involve inherent risks and
uncertainties,
both general and specific, whether known or unknown, and/or any other
factor
that may materially differ from the plans, objectives, expectations,
estimates
and intentions expressed or implied in such forward-looking statements.
Such may
in particular cause actual results with allosteric modulators of mGluR2,
mGluR4,
mGluR5, GABABR, FSHR/LHR, GLP1R, TNFR1, RTK, TrkB or other therapeutic
targets
to be materially different from any future results, performance or
achievements
expressed or implied by such statements. There can be no guarantee
that
allosteric modulators of mGluR2, mGluR4, mGluR5, GABABR, FSHR/LHR, GLP1R,
TNFR1,
RTK, TrkB or other therapeutics targets will be approved for sale in any
market
or by any regulatory authority. Nor can there be any guarantee that
allosteric
modulators of mGluR2, mGluR4, mGluR5, GABABR, FSHR/LHR, GLP1R, TNFR1,
RTK,
TrkB or other therapeutic targets will achieve any particular levels of
revenue
(if any) in the future. In particular, management's expectations
regarding
allosteric modulators of mGluR2, mGluR4, mGluR5, GABABR, FSHR/LHR,
GLP1R,
TNFR1, RTK, TrkB or other therapeutic targets could be affected by, among
other
things, unexpected actions by our partners, unexpected regulatory
actions or
delays or government regulation generally; unexpected clinical trial
results,
including unexpected new clinical data and unexpected additional
analysis of
existing clinical data; competition in general; government, industry and
general
public pricing pressures; the company's ability to obtain or maintain
patent or
other proprietary intellectual property protection. Should one or more of
these
risks or uncertainties materialize, or should underlying assumptions
prove
incorrect, actual results may vary materially from those anticipated,
believed,
estimated or expected. Addex Pharmaceuticals Ltd is providing the
information in
this press release as of this date and does not undertake any
obligation to
update any forward-looking statements contained in this press release
as a
result of new information, future events or otherwise, except as may be
required
by applicable laws.
This announcement is distributed by Thomson Reuters on behalf of
Thomson Reuters clients. The owner of this announcement warrants that:
(i) the releases contained herein are protected by copyright and
other applicable laws; and
(ii) they are solely responsible for the content, accuracy and
originality of the information contained therein.
Source: Addex Pharmaceuticals via Thomson Reuters ONE
[HUG#1566912]
