1-Substituted 4-(3-Hydroxyphenyl)piperazines Are Pure Opioid Receptor Antagonists

Carroll, F. Ivy; Cueva, Juan Pablo; Thomas, James B.; Mascarella, S. Wayne; Runyon, Scott P.; Navarro, Hernán A.

doi:10.1021/ml100126b

Cited by 9 publications

(39 citation statements)

References 26 publications

(54 reference statements)

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“…31 The piperazine analogues of ( S )-1,3-dimethyl-4-(3-hydroxyphenylpiperazine ( 36a ) (Chart 3), which is a piperazine analogue of 2b , was a pure non-selective opioid receptor antagonist. Zimmerman and co-workers reported that replacement of the N -methyl group in 2b with an N -phenylpropyl group resulted in the more potent non-selective pure opioid receptor antagonist 2c .…”

Section: Resultsmentioning

confidence: 99%

“…The piperazine JDTic-like analogue 10b was synthesized by a procedure similar to that used for 10a starting with (2 R )-1- tert -butoxycarbonyl-4-(3-methoxyphenyl)-3-methylpiperazine ( 17 ) 31 as outlined in Scheme 2. Treatment of 17 31 with 1 N hydrochloric acid in tetrahydrofuran gave 18 .…”

Section: Chemistrymentioning

confidence: 99%

“…Treatment of 17 31 with 1 N hydrochloric acid in tetrahydrofuran gave 18 . Coupling of 18 with tert -butoxycarbonyl-L-valine using BOP in tetrahydrofuran containing triethylamine followed by reduction of the intermediate amide with borane•dimethylsulfide [BH 3 •S(CH 3 ) 2 ] in tetrahydrofuran and removal of the tert -butoxycarbonyl protecting group with 6 N hydrochloric acid yielded 19 .…”

Section: Chemistrymentioning

confidence: 99%

“…30 We recently reported the discovery of 3-(4-substituted piperazin-1-yl)phenols ( 9 ) (Chart 2) as a new class of opioid receptor antagonists. 31 These compounds were found to be relatively nonselective opioid receptor antagonists. Thus, their opioid receptor properties are more like those of naloxone ( 1a ), naltrexone ( 1b ), and the originally reported N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines ( 2b–d ).…”

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Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

et al. 2013

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There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [35S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [35S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [35S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.

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Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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confidence: 99%

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Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

et al. 2013

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“…As shown in Scheme 4 , the N-arylation 15 of N -methylpiperazine 20 with 3-bromoanisole afforded 21 . Deprotection with boron tribromide gave compound 8a .…”

Section: Chemistrymentioning

confidence: 99%

Effect of the 3- and 4-Methyl Groups on the Opioid Receptor Properties of N-Substituted trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines

et al. 2014

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N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a–b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a–b, we synthesized analogues of 2a–b which lacked the 4-methyl (5a–b), 3-methyl (6a–b) and both the 3- and 4-methyl group (7a–b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were non-selective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts and (3) compounds 2a–b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogs 5a–b, 6a–b and 7a–b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a–b) gives (4a–b) which are opioid antagonists.

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3‐[3‐(Phenalkylamino)cyclohexyl]phenols: Synthesis, biological activity, and in silico investigation of a naltrexone‐derived novel class of MOR‐antagonists

Tocco

Laus

Vanejevs

et al. 2022

Archiv der Pharmazie

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The development of novel μ-opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3-[3-(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGOinduced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra-Precision Glide and Generalized-Born Surface Area experiments provided useful information on the nature of the ligand-receptor interactions, indicating a peculiar combination of C-1 stereochemistry and N-substitutions as feasibly essential for MOR-ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR-ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3-cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds.[ 3 H]DAMGO binding assay, 3-[3-(phenalkylamino)cyclohexyl]phenols, GTPγS assay, in silico study, MOR antagonists 1 | INTRODUCTION Despite the serious and potentially fatal adverse effects, μ-opioid receptor (MOR) agonists such as morphine, oxycodone, and fentanyl, have been over/misprescribed in recent years, resulting in a dramatic increase in opioid dependence, illegal opioid use, and opioid-related deaths. Opioid antagonists are a class of drugs that bind competitively to one or more of the opioid receptors, present little or no intrinsic activity, and robustly antagonize the effects of receptor agonists. They are utilized as antidotes for opioid overdose (naloxone) and approved for the treatment of opioid and alcohol dependence (naltrexone). Several structural classes have been identified as MOR antagonists with variable

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1-Substituted 4-(3-Hydroxyphenyl)piperazines Are Pure Opioid Receptor Antagonists

Cited by 9 publications

References 26 publications

Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

Effect of the 3- and 4-Methyl Groups on the Opioid Receptor Properties of N-Substituted trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines

3‐[3‐(Phenalkylamino)cyclohexyl]phenols: Synthesis, biological activity, and in silico investigation of a naltrexone‐derived novel class of MOR‐antagonists

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