Parası kalmadığı için otobüse binemiyordur ailesi porno izle ona daha yeni para gönderdiği için tekrar porno istemeye utanınca mecburen otostop çekmek için youporn çantasını alarak yol kenarına gelir etekli porno liseli türk kız yol kenarında dururken yanına yaklaşan porno kibar bir gencin onu gideceği yere kadar bırakmak porno izle istemesine çok mutlu olur arabaya bindiklerinde gideceği yer ile porno arabayı kullanan adamın gittiği yer arasında çok mesafe sex izle farkı olduğunu anlayan türk kız bu yaptığı porno indir iyilik karşısında arabada ona memelerini açar porno sapıklaşan adam yol kenarındaki hotelde durarak porno izle üniversiteli otostop çeken türk kızına odada sakso çektirip sikerSimultaneous MOR/DOR targeting as useful strategy for pain management| Abstract

44 7460 854 031

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Abstract

Simultaneous MOR/DOR targeting as useful strategy for pain management

Author(s): Rita Turnaturi

Opioid analgesics, such as morphine, elicit analgesic effects primarily through mu opioid receptor (MOR), whose activation determines not only analgesia but also a sequel of unwanted side effects. Although indispensable for the management of acute severe pain, the classical analgesics are unsuccessful for inflammatory and neuropathic pain treatment. Multitarget MOR/delta opioid receptor (DOR) agonists, showing synergic antinociceptive activity with low side-effects induction in preclinical models, represent a strategy to overcome the default in chronic pain treatment. In this context, we identified the multitarget MOR/DOR ligand LP2 characterized by high MOR (Ki= 1.08 nM) and DOR (Ki= 6.6 nM) affinity coupled to an agonist profile versus these receptors (IC50MOR= 21.5 nM and IC50DOR= 4.4 nM). In tail flick test, LP2 produced a long-lasting antinociception naloxone-reversed (ED50 of 0.9 mg/kg i.p.). Building upon these evidences, our efforts were focused on demonstrating whether the LP2 multitarget profile could be useful for persistent pain states. Thus, LP2 is evaluated in a model of neuropathic pain induced by chronic constriction injury (CCI) and a model of inflammatory pain (Formalin test). Moreover, both 2R- and 2S- diastereoisomers of LP2 were synthesized in order to investigate the role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold in drug-opioid receptor interaction. Their pharmacological profile were compared each other and with LP2. Specifically, 2S-LP2 showed an increased antinociceptive effect than LP-2 consistent with the in vitro functional profile. Moreover, 2S-LP2 resulted a biased MOR/DOR agonist with functional selectivity for G-protein signaling and reduced β-arrestin 2 recruitment, an effectiveness profile in chronic pain conditions management.


Share this