Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric 5-(3-Hydroxyphenyl)morphans

Cheng, Kejun; Lee, Yong Sok; Rothman, Richard B.; Dersch, Christina M.; Bittman, Ross W.; Jacobson, Arthur E.; Rice, Kenner C.

doi:10.1021/jm1011676

Cited by 17 publications

(13 citation statements)

References 19 publications

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“…Human h MOR-expressing CHO cells were generated and examined for [ 35 S]GTPγS binding as described recently [46]. The procedures were generally as described above for HEK 293-MOR cells with the following exceptions; homogenization of cells was carried out in the presence of a protease inhibitor cocktail, incubation mixtures contained additionally 1 mM DDT, and incubation was initiated with test drugs and [ 35 S]GTPγS together for a total time of 3 h at 25°C.…”

Section: Methodsmentioning

confidence: 99%

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

et al. 2013

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ObjectiveThe iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.MethodsIbogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.Results And SignificanceIn rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

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Section: Methodsmentioning

confidence: 99%

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

et al. 2013

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“…22 As shown in Scheme 6, coupling of ketone 2 with a chiral cyclopropyl carboxylic acid generated the intermediate methoxyphenyl amides (Scheme 7). Subsequent stereoselective reduction of the 9-oxo to the alcohol (Scheme 8), followed by reduction of the amide and conversion to the phenol, should provide the desired products.…”

Section: Resultsmentioning

confidence: 99%

“…20 Notably, the 9β-OH substitution changed the μ-antagonist activity of 5-(3-hydroxyphenyl)- N -phenylethylmorphan 21 to a potent μ-agonist. In a different study, 22 we also pointed out that 5-phenylmorphan enantiomers with some restrained N-substituents could act as very potent μ-antagonists while others were inverse agonists. The conformational restraint was introduced by a cyclopropyl ring or through introduction of unsaturation in an N-substituent’s alkyl chain.…”

Section: Introductionmentioning

confidence: 82%

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

Truong

Hassan

Lee

et al. 2017

Bioorganic & Medicinal Chemistry

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The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(−) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the μ,-opioid receptor (e.g., 1R,5R,9S-16: Ki = 0.073, 0.74, and 1.99 nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy μ-agonists (EC50 = 0.74 and 18.5 nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S, 5S,9R-16 was unusual, it had good affinity for the μ-OR (Ki = 26.5 nM) and was an efficacious μ-antagonist (Ke = 29.1 nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16 μ-agonist and the previously synthesized (1R,5R,9S)-(−)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(−)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.

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“…DCM was preliminarily distilled over NaOH. 2-Arylcyclopropylethanones, arylidenacetones, 2-methylcyclopropylethanone, and ( R , R )-2-phenylcyclopropylethanone , were synthesized according to the literature procedures.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Branched Tryptamines via the Domino Cloke–Stevens/Grandberg Rearrangement

et al. 2016

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The rearrangement of cyclopropylketone arylhydrazones generated in situ from arylhydrazine hydrochlorides and ketones leads to formation of tryptamine derivatives. The use of (2-arylcyclopropyl)ethanones in the reactions with model 4-bromophenylhydrazine hydrochloride gives branched tryptamines with aryl groups in the α-position to the amino group, while (2-methylcyclopropyl)ethanone gives a mixture of α- and β-substituted products in a ratio of 1:3. The method was found effective in the synthesis of enantiomerically pure tryptamine. Thus, (R,R)-(2-phenylcyclopropyl)ethanone gives the (S)-α-phenyltryptamine derivative with an enantiomeric excess over 99%.

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Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric 5-(3-Hydroxyphenyl)morphans

Cited by 17 publications

References 19 publications

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

Synthesis of Branched Tryptamines via the Domino Cloke–Stevens/Grandberg Rearrangement

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