Analysis of possible allosteric modulation of opioid signaling

• Autorzy: Bartuzi D. , Kaczor A. , Kijkowska-Murak U. , Fidecka S. , Kedzierska E. , Matosiuk D.
• Języki publikacji: EN

Abstrakty

EN

Administration of classic orthosteric ligands of opioid receptors, like morphine, apart from inducing significant therapeutic effects such as analgesia, presents many disadvantages, with drug addiction and impairment of the breathing centre on the first place. However, allosteric modulation of these receptors could offer better selectivity among receptor subtypes and preservation of the physiological pattern of activation [1]. All in all, such compounds could bring more advantageous pharmacological profile, and decrease possibility of undesirable side effects. The aim of work was to investigate the mode of interaction of the unique ligands [2-5] with MOR and DOR opioid receptors. As premises of allosteric pockets existence appeared, establishment of a possible mode of interaction between ortho- and allosteric pocket became an consecutive aim. Models of the receptors were obtained with the method of homology modelling, using β2-adrenergic receptor as a template. These models were initially verified by rigid docking of rigid opiod receptors’ ligands (SIOM and naloxone). Best protein models were chosen for flexible dockings. Analysis of the results revealed that investigated compounds could be bound into two different pockets on the extracellular receptor’s surface near the orthosteric pocket. Location of those hypothetical binding sites suggests, that their interaction with ligands could significantly modulate function of the receptor. The hypothetical pocket located between extracellular parts of TM1, TM2 and TM7 seems to share important amino acids with orthosteric pocket. Moreover, the other hypothetical binding site is located in ECL2 region, and seems to be analogous to allosteric binding site discovered in muscarinic M2 receptor structure [6].

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: 1
• Opis fizyczny: p.167

Twórcy

autor

Bartuzi D.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

autor

Kaczor A.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

autor

Kijkowska-Murak U.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

autor

Fidecka S.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

autor

Kedzierska E.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

autor

Matosiuk D.

• Department of Synthesis and Chemical Technology of Medicinal Substances, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland

Bibliografia

• [1] May, L. T.; Christopoulos, A. Curr. Opin. Pharmacol. 2003,
• [2] Matosiuk, D.; Fidecka, S.; Antkiewicz-Michaluk L.; Dybała, I.; Kozioł, A. E, Eur. J. Med. Chem. 2001,
• [3] Matosiuk, D.; Fidecka, S.; Antkiewicz-Michaluk, L.; Lipkowski, J.; Dybala, I.; Koziol, A. E. Eur. J. Med. Chem. 2002,
• [4] Matosiuk, D.; Fidecka, S.; Antkiewicz-Michaluk, L.; Dybala, I.; Koziol, A. E. Eur. J. Med. Chem. 2002,
• [5] Sztanke, K.; Fidecka, S.; Kędzierska, E.; Karczmarzyk, Z.; Pihlaja, K.; Matosiuk, D. Eur. J. Med. Chem. 2005,
• [6] May, L. T.; Avlani, V. A.; Langmead, C. J.; Herdon, H. J.; Wood, M. D.; Sexton, P. M.; Christopoulos, A. Mol. Pharmacol. 2007,