Group leader: Sándor Benyhe        

Email:benyhe.sandor[at]brc.hu

Group website:

Group members

Name

Title

 

 

Sándor BENYHE

scientific advisor

publications

CV

 

Ferenc ÖTVÖS

senior research associate

publications

CV

 

Edina SZŰCS

research associate

publications

CV

 

Zsuzsa BENYHE

scientific administrator / technician

 

 

Research                                  

 

The success of mechanism-based drug discovery depends on the definition of the drug target. Major protein families as drug targets are GPCRs (33%), ion channels (18%) and nuclear receptors (16%).  G-protein coupled receptors (GPCRs), also called seven transmembrane spanning receptors (7TMRs), represent the largest family of cell surface receptors and are the targets of intense drug discovery and developmental efforts. While a number of available drugs on the market target GPCR signaling pathways, overall less than 20% of known GPCRs are targeted.  Ubiquitous receptors, these seven transmembrane-spanning proteins transduce extracellular signals for ligands as diverse as ions, photons of light, odorants, hormones, neurotransmitters and peptides into intracellular signaling cascades. Over 800 human GPCRs have been identified to date with five major families. Despite intense drug discovery and development efforts, clinically useful drugs do not exist for the large majority of these receptors. Our group focuses on the mechanisms of action of the multiple opioid (four members: m, d, k and N/OFQ, or using different nomenclature: MOPr, DOPr, KOPr and NOPr)  and the two types of cannabinoid (CB1 and CB2) receptors. In addition to the need for scientific knowledge, the driving force of our studies is the research into the widespread use of opioids and cannabinoids and their harmful biomedical and social consequences. Nowadays the misuse of and addiction to opioids include prescription opioids, street heroin, and illicitly manufactured fentanyl, a powerful synthetic opioid. Rapid and increasing production of ’designer drugs’ with unknown chemical structures and illegal trafficking of opium and heroin remained significant worldwide. In addition to certain cannabinoids (mainly the psychotropic component of the hemp plant, D9-THC, i.e. tetrahydrocannabinol), which are known to have harmful effects, the use of medical cannabis preparations (e.g., cannabidiol) has recently gained widespread acceptance, accompanied by much attention and social debate. Classic agonist and antagonist ligands that act at GPCRs tend to bind to the receptor's orthosteric site, that is, the site recognized by the endogenous agonist for that receptor. The discovery of allosteric modulators of GPCRs provides a promising new strategy for drug development. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Ligands that have two distinct binding properties can be found under different names; bivalent and bifunctional. A bifunctional ligand is a non-selective compound that acts at two different protein targets and thus presents two distinct binding properties.  A bivalent ligand is a compound that possesses two distinct pharmacophores, those are covalently  interconnected with chemical spacer. There are so-called bitopic ligands that interact with both the allosteric and orthosteric sites of the same receptor protein. In recent years, our team has been involved in the design and research and development of multitarget molecules with diverse chemical structures, including synthetic hybrid peptides. Several other bifunctional ligands have been characterized by in vitro receptor biochemical and in silico molecular docking methods. In addition to our domestic partners, we collaborated mainly with Polish and Italian researchers. Research and development of drugs acting on G-protein coupled receptors remains a promising scientific task.

 

Key words of the group:   Papaver somniferum, Cannabis indica, endogenous opioid peptides, endocannabinoids, protein chemistry, GPCR, regulatory G-proteins, narcotics, psychoacive compounds, ligand-receptor interaction, radioligands, receptor binding, opioids, cannabinoids, receptor-receptor  interactions, signal transduction, tolerance, dependence, drug addiction, molecular docking, structure-activity relationship, neuropeptides, chemical biodiversity, hybrid oligopeptides, bifunctional ligands, multitarget compounds, isothermal titration calorimetry.

Schematic view of highly conserved heptahelical structural features in the GPCR superfamily

 

3D model for the MOP receptor (left)

Binding pocket and receptor surfaces of the MOP receptor (right)

 

Selected publications

1) Szűcs, Edina ; Marton, János ; Szabó, Zoltán ; Hosztafi, Sándor ; Kékesi, Gabriella ; Tuboly, Gábor ; Bánki, László ; Horváth, Gyöngyi ; Szabó, Pál T. ; Tömböly, Csaba ; Benyhe, Sándor et al.
Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 191 Paper: 112145 , 15 p. (2020)

 

2) Szűcs, Edina ; Stefanucci, Azzurra ; Dimmito, Marilisa Pia ; Zádor, Ferenc ; Pieretti, Stefano ; Zengin, Gokhan ; Vécsei, László ; Benyhe, Sándor ; Nalli, Marianna ; Mollica, Adriano
Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists.
BIOMOLECULES 10 : 2 Paper: 284 , 18 p. (2020)

 

3) Zádor, F. ; Mohammadzadeh, A. ; Balogh, M. ; Zádori, Z.S. ; Király, K. ; Barsi, S. ; Galambos, A.R. ; László, S.B. ; Hutka, B. ; Váradi, A. ; Benyhe, S. et al.
Comparisons of in Vivo and in Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate
MOLECULES 25 : 6 Paper: 1370 , 22 p. (2020)

 

4) Kudla, Lucja ; Bugno, Ryszard ; Skupio, Urszula ; Wiktorowska, Lucja ; Solecki, Wojciech ; Wojtas, Adam ; Golembiowska, Krystyna ; Zador, Ferenc ; Benyhe, Sandor ; Buda, Szymon et al.
Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine
BRITISH JOURNAL OF PHARMACOLOGY 176 : 23 pp. 4434-4445. , 12 p. (2019)

 

5) Erdei, AI ; Borbely, A ; Magyar, A ; Taricska, N ; Perczel, A ; Zsiros, O ; Garab, G ; Szucs, E ; Otvos, F ; Zador, F ; Benyhe, S et al.
Biochemical and pharmacological characterization of three opioid-nociceptin hybrid peptide ligands reveals substantially differing modes of their actions.
PEPTIDES 99 pp. 205-216. , 12 p. (2018)

 

6) Mollica, A ; Pelliccia, S ; Famiglini, V ; Stefanucci, A ; Macedonio, G ; Chiavaroli, A ; Orlando, G ; Brunetti, L ; Ferrante, C ; Pieretti, S ; Benyhe, S et al.
Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 32 : 1 pp. 444-451. , 8 p. (2017)

 

7) Stefanucci, A ; Carotenuto, A ; Macedonio, G ; Novellino, E ; Pieretti, S ; Marzoli, F ; Szucs, E ; Erdei, AI ; Zador, F ; Benyhe, S et al.
Cyclic Biphalin Analogues Incorporating a Xylene Bridge: Synthesis, Characterization, and Biological Profile
ACS MEDICINAL CHEMISTRY LETTERS 8 : 8 pp. 858-863. , 6 p. (2017)

 

8) Kleczkowska, P ; Hermans, E ; Kosson, P ; Kowalczyk, A ; Lesniak, A ; Pawlik, K ; Bojnik, E; Benyhe, S ; Nowicka, B ; Bujalska-Zadrozny, M ; Benyhe, S et al.
Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents
BRAIN RESEARCH 1648 pp. 172-180. , 9 p. (2016)

 

9) Kowalczyk, A ; Kleczkowska, P ; Rękawek, M ; Kulik, K ; Lesniak, A ; Erdei, A ; Borics, A ; Martin, C ; Pawlik, K ; Lipkowski, AW; Benyhe, S et al.
Biological evaluation and molecular docking studies of AA3052, a compound containing a μ-selective opioid peptide agonist DALDA and d-Phe-Phe-d-Phe-Leu-Leu-NH2, a substance P analogue
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 93 pp. 11-20. , 10 p. (2016)

 

10) Benyhe, S ; Zador, F ; Otvos, F
Biochemistry of opioid (morphine) receptors: binding, structure and molecular modelling
ACTA BIOLOGICA SZEGEDIENSIS 59 : Suppl 1 pp. 17-37. , 21 p. (2015)

 

11) Mollica, A ; Costante, R ; Novellino, E ; Stefanucci, A ; Pieretti, S ; Zador, F ; Samavati, R ; Borsodi, A ; Benyhe, S ; Vetter, I et al.
Design, Synthesis and Biological Evaluation of Two Opioid Agonist and Ca 2.2 Blocker Multitarget Ligands.
CHEMICAL BIOLOGY & DRUG DESIGN 86 : 2 pp. 156-162. , 7 p. (2015)

 

12) Zádor, F  ; Lénárt, N ; Csibrány, B ; Sántha, M ; Molnár, M ; Tuka, B ; Samavati, R ; Klivényi, P ; Vécsei, L ; Marton, A ; Benyhe, S et al.
Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner.
NEUROPHARMACOLOGY 89 pp. 298-307. , 10 p. (2015)