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Addex Pharmaceuticals (ADXN.SW) Scientists Discover Glucagon-like-peptide-1 (GLP-1) Induced Interaction Between GLP-1 and Gastric Inhibitory Peptide (GIP) Receptors


11/28/2011 9:15:42 AM

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]


Chris Maggos
Business Development & Communication
Addex Pharmaceuticals
+41 22 884 15 11
Email Contact



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