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Endogenous and exogenous opiates are currently considered the drugs of choice for treating different kinds of pain. However, their prolonged use produces several adverse symptoms, and in addition, many forms of pain are resistant to any kind of therapy. | ỊFEBS Journal Investigation of the interaction between the atypical agonist c YpwFG and MOR Luca Gentilucci1 Federico Squassabia1 Rossella Demarco1 Roberto Artali2 Giuliana Cardillo1 Alessandra Tolomelli1 Santi Spampinato3 and Andrea Bedini3 1 Dipartimento di Chimica G. Ciamician Universita degli Studi di Bologna Italy 2 Istituto di Chimica Farmaceutica e Tossicologica P. Pratesi University di Milano Italy 3 Dipartimento di Farmacologia Universita degli Studi di Bologna Italy Keywords atypicalagonist cyclopentapeptide induced fit molecular docking opioid receptor Correspondence L. Gentilucci Dipartimento di Chimica G. Ciamician University degli Studi di Bologna via Selmi 2 40126-Bologna Italy Fax 39 051 2099456 Tel 39 051 2099462 E-mail luca.gentilucci@unibo.it Received 8 January 2008 revised 22 February 2008 accepted 6 March 2008 doi 10.1111 j.1742-4658.2008.06386.x Endogenous and exogenous opiates are currently considered the drugs of choice for treating different kinds of pain. However their prolonged use produces several adverse symptoms and in addition many forms of pain are resistant to any kind of therapy. Therefore the discovery of compounds active towards Lt-opioid receptors MORs by alternative pharmacological mechanisms could be of value for developing novel classes of analgesics. There is evidence that some unusual molecules can bind opioid receptors albeit lacking some of the typical opioid pharmacophoric features. In particular the recent discovery of a few compounds that showed agonist behavior even in the absence of the primary pharmacophore namely a protonable amine led to a rediscussion of the importance of ionic interactions in stabilizing the ligand-receptor complex and in activating signal transduction. Very recently we synthesized a library of cyclic analogs of the endogenous MOR-selective agonist endomorphin-1 YPWF-NH2 containing a Gly5 bridge between Tyr1 and Phe4. The cyclopeptide c YpwFG showed good affinity and agonist behavior. This .