The dimethyl alkylationĪ worse MOR binding profile. A third methyl group in positionĤ′ ( 7b), as well as an ethyl group in positionĦ′ ( 7d), reduced MOR affinity by 6- and 2-timesĬompared to 7a and 7e. Respectively, possessed the highest MOR affinity, followed by derivatives 7b, 7d, and 7c, having slightly Having methyl groups in positions 2′,6’ and 2′,5′, Of LP2 was found to be a potent G-protein biased MOR/DOR agonist withĭerivatives showed a broad range of binding affinityįor MOR (K i = 7.4–1,540 nM) and low or no affinity Of a significant long-lasting antinociceptive effect, 23− 25 was developed through the introduction of the short and flexibleĢ R/ S-methoxy ethyl spacer as N-substituent (LP2 4, Figure Figure1 1). 22 More recently, a dual MOR/DOR agonist, endowed Group affected the shift from MOR agonism to antagonism. Of the aromatic moiety with an indoline, tetrahydroquinoline or diphenylamine 21 Analogously, the increased steric hindrance Ring ( 3, Figure Figure1 1) switched the MOR efficacy profile from agonism to antagonism. 19, 20 The phenyl replacement with the bulkier N-naphthyl Pain with low tolerance-inducing capability. Substituent, resulted in vitro and in vivo a potent MOR agonist/DOR antagonist 18 able to counteract nociceptive pain and behavioral signs of persistent In particular, LP1 ( 2, Figure Figure1 1), with an N-phenylpropanamido With the N-acetamido one was detrimental for MOR,ĭOR, and KOR recognition, 17 while an N-propanamido spacer improved the opioid binding profile. 16 The replacement of the N-ethylamino spacer Group as N-substituent conferred a MOR agonist profile in vitro and in vivo ( 1, Figure Figure1 1). Of a tertiary N-methyl- N-phenylethylamino While β-arrestin recruitment is responsible for opioid sideĪ versatile template 14, 15 for the development of a specificįunctional profile by modifying N-substituent orĨ-OH group. That opioid compounds promoting G-protein signaling produce analgesia,
Of biased agonists, 10 able to differentiallyĪctivate GPCR downstream pathways, becameĪ new approach in the design of novel drug candidates. Propensity to produce tolerance and physical dependence was reportedįor both dual MOR/DOR agonist 4− 6 and MOR agonist/DOR antagonist 1− 3 For instance, a valid analgesic effect with lower
Strategy to overcome the typical side effects associated with opioid Were made to develop effective multitarget opioid ligands as an alternative
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