Cinnamoyl Derivatives of 7α-Aminomethyl-6,14-<i>endo</i>-ethanotetrahydrothebaine and 7α-Aminomethyl-6,14-<i>endo</i>-ethanotetrahydrooripavine and Related Opioid Ligands

Rennison, David; Neal, A P; Cami‐Kobeci, Gerta; Aceto, Mario D.; Martinez-Bermejo, Fernando; Lewis, John W.; Husbands, Stephen M.

doi:10.1021/jm070255o

Cited by 16 publications

(20 citation statements)

References 16 publications

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“…These compounds engendered primarily saline-lever responding up to doses that either significantly reduced response rates or induced untoward side effects (e.g., convulsions). We are not aware of any other studies that have administered these particular opioid receptor agonists to ethanol discriminating subjects, however, we selected these compounds based on their known selectivity and/or efficacy profiles at mu and/or delta opioid receptors (e.g., fentanyl: mu opioid receptor full agonist, ~ 100- to 250-fold selective for mu vs. delta, Emmerson et al, 1994; Jagerovic et al, 2002; buprenorphine: mu opioid receptor partial agonist, ~ 3- to 15-fold selective for mu vs. delta, and kappa opioid receptor antagonist, Rennison et al, 2007; Spagnolo et al, 2008; SNC 80: delta opioid receptor full agonist, ~ 800- to 900-fold selective for delta vs. mu, Knapp et al, 1996; Codd et al, 2009; SNC 162: partial agonist, > 1000-fold selective for delta vs. mu, Knapp et al, 1996). Our results, however, are in general concordance with other studies reporting a lack of substitution of the mu opioid receptor agonist morphine for the discriminative stimulus effects of ethanol in monkeys and rats (Winter, 1975; York and Bush, 1982; Bowen et al, 1997; Kosten et al, 1999; Platt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Platt

Bano

2011

European Journal of Pharmacology

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Mu and delta opioid receptors modulate the reinforcing effects of ethanol, however, their role in the subjective effects of ethanol is not well understood. This study evaluated the contribution of mu and delta opioid receptors to the subjective effects of ethanol using drug discrimination procedures. Monkeys were trained to discriminate ethanol from saline under a schedule of food delivery. In tests, ethanol engendered increases in drug-lever responding, reaching a maximum of >80%. The mu opioid receptor agonists fentanyl and buprenorphine and the delta opioid receptor agonists SNC 80 and SNC 162 did not substitute for the discriminative stimulus effects of ethanol. As pretreatments, the full agonists fentanyl and SNC 80 enhanced the effects of low doses of ethanol and fentanyl attenuated the effects of the ethanol training dose. Although the possibility of pharmacological antagonism of the effects of ethanol cannot be ruled out, a more likely alternative is that the diminished effects of ethanol were due to perceptual masking of the ethanol stimulus. In contrast, the partial agonists buprenorphine and SNC 162 did not alter ethanol’s effects. Finally, the discriminative stimulus effects of ethanol were attenuated following administration of presumably mu-selective doses of the antagonist naltrexone, but not after administration of the delta opioid receptor antagonist naltrindole. The ability of naltrexone to block the discriminative stimulus effects of ethanol likely reflects its capacity to attenuate ethanol-induced increases in endogenous opioids, in particular beta-endorphin, because attenuation of the ethanol stimulus was not accompanied by significant suppression of response rate.

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Section: Discussionmentioning

confidence: 99%

Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Platt

Bano

2011

European Journal of Pharmacology

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“…Several structure-activity relationship (SAR) studies have shown that the 6,14-bridged oripavines with a cyclopropylmethyl group at N 17 , such as diprenorphine, buprenorphine, and naltrexone, might possess some morphine-antagonist characteristics. Replacing this group with a methyl group has been found to greatly increase the efficacy of compounds, particularly at the µ-and κ-opioid receptors [11,12] . We also considered that the mixed ORL1/µ-opioid receptor activity of 030418 may have an attractive profile for the treatment of pain and addiction, similar to SR16435 and buprenorphine [32,33] .…”

Section: Discussionmentioning

confidence: 99%

“…Many compounds obtained from the structural modification of buprenorphine have also been extensively developed [6,11,12] . Inspired by these reports, N-cyclopropylmethyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (thienorphine, Figure 1) was synthesized in our institute [13] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Wen¹,

Yu²,

Li³

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine. Methods: The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5′-O-(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations. Results: The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K i values in the nanomolar range. In [ 35 S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing. Conclusion:The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N 17 position and the high hydrophobicity of the C 7 -thiophene group in its chemical structure.

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“…36 A solution of oxime 6 (0.58 g; 2.4 mmol) in anhydrous THF (10 mL) was added dropwise to a suspension of LiAlH 4 (0.23 g, 6.0 mmol) in the same solvent (10 mL). The resulting mixture was stirred for 24 h at room temperature.…”

Section: Reduction Of Oxime 6 To Aminementioning

confidence: 99%

Synthesis, structure and antiproliferative activity of chiral polyamines based on a 2-azanorbornane skeleton

Kamińska

Wojaczyńska

Wietrzyk

et al. 2016

Tetrahedron: Asymmetry

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Cinnamoyl Derivatives of 7α-Aminomethyl-6,14-endo-ethanotetrahydrothebaine and 7α-Aminomethyl-6,14-endo-ethanotetrahydrooripavine and Related Opioid Ligands

Cited by 16 publications

References 16 publications

Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Synthesis, structure and antiproliferative activity of chiral polyamines based on a 2-azanorbornane skeleton

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