Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

Neumeyer, John L.; Zhang, Bin; Zhang, Tangzhi; Sromek, Anna W.; Knapp, Brian I.; Cohen, Dana J.; Bidlack, Jean M.

doi:10.1021/jm3001086

Cited by 9 publications

(4 citation statements)

References 28 publications

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“…Given the wide chemical (structural) and pharmacological diversity of KOR targeting drugs that have been reported, and the two classes of KOR PET radiotracers available (phenylacetamide, KOR agonist; benzyloxyarylamide, KOR antagonist), we measured KOR agonist drug occupancy with [ 11 C]GR103545 and compared results to [ 11 C]LY2795050 and [ 11 C]LY2459989 (Table ). Butorphan (MCL-101) is a full agonist at KORs, derived from the morphinan class of opioids . Our results with morphinan KOR antagonists (i.e., naloxone, naltrexone) demonstrated complete blockade of radiotracer-specific binding, as anticipated.…”

Section: Results and Discussionsupporting

confidence: 77%

“…Butorphan (MCL-101) is a full agonist at KORs, derived from the morphinan class of opioids. 65 Our results with morphinan KOR antagonists (i.e., naloxone, naltrexone) demonstrated complete blockade of radiotracer-specific binding, as anticipated. Butorphan was chosen because of its structural BP ND (reduced to 34% of baseline from 1 mg/kg butorphan).…”

Section: C]gr103545 (See Supporting Information (Si) For Time− Activi...supporting

confidence: 80%

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Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging

Placzek

Schroeder

Che

et al. 2018

ACS Chem. Neurosci.

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Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BP, binding potential with respect to non-displaceable uptake). This prompted us to systematically look at the relationships between baseline BP maps for three common KOR PET radioligands, the antagonists [C]LY2795050 and [C]LY2459989, and the agonist [C]GR103545. We then measured changes in BP using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BP was affected similarly between [C]GR103545 and [C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined, and we observed a persistent decrease in [C]GR103545 BP up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [C]GR103545 BP but did not change [C]LY2459989 binding. This discrepancy was further examined in dose-response studies with each radiotracer as well as in vitro binding experiments.

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Section: Results and Discussionsupporting

confidence: 77%

Section: C]gr103545 (See Supporting Information (Si) For Time− Activi...supporting

confidence: 80%

Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging

Placzek

Schroeder

Che

et al. 2018

ACS Chem. Neurosci.

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“…KOH) to yield 7β-norbuprenorphine (180). Subsequently, the secondary amine was alkylated with cyclopropylmethyl bromide to yield the 7β-N 17 -cyclopropylmethyl derivative (181), which in turn was 3-O-demethylated with KOH in diethylene glycol at 210 • C to provide 7β-buprenorphine (166) in an overall yield of 7.1% from the 7β-dihydrothevinone (164) starting material.…”

Section: Isomerizationmentioning

confidence: 99%

“…The free 3-phenolic hydroxyl group was long thought to be essential for the pharmacological effect of morphinan ligands. Contrary to this expectation, a number of compounds with high OR binding affinities have been developed by the research group of Neumeyer [90,166,167] in the last two decades by bioisoteric replacement of the 3-phenolic hydroxyl group with an aminothiazole moiety, or by modification to oxazole, carbamate, urea, aminobenzyl, and aminophenyl derivatives. In general, the 3-O-demethylation of morphine alkaloids has proven difficult; the slow rate of demethylation call for long reaction times and harsh reaction conditions often lead to decomposition, tedious work-up, and poor chemical yields.…”

Section: -O-demethylationmentioning

confidence: 99%

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

et al. 2022

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6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.

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Multifunctional Opioid Ligands

Anand

Montgomery

2018

Handbook of Experimental Pharmacology

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The opioid receptor system plays a major role in the regulation of mood, reward, and pain. The opioid receptors therefore make attractive targets for the treatment of many different conditions, including pain, depression, and addiction. However, stimulation or blockade of any one opioid receptor type often leads to on-target adverse effects that limit the clinical utility of a selective opioid agonist or antagonist. Literature precedent suggests that the opioid receptors do not act in isolation and that interactions among the opioid receptors and between the opioid receptors and other proteins may produce clinically useful targets. Multifunctional ligands have the potential to elicit desired outcomes with reduced adverse effects by allowing for the activation of specific receptor conformations and/or signaling pathways promoted as a result of receptor oligomerization or crosstalk. In this chapter, we describe several classes of multifunctional ligands that interact with at least one opioid receptor. These ligands have been designed for biochemical exploration and the treatment of a wide variety of conditions, including multiple kinds of pain, depression, anxiety, addiction, and gastrointestinal disorders. The structures, pharmacological utility, and therapeutic drawbacks of these classes of ligands are discussed.

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Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

Cited by 9 publications

References 28 publications

Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging

Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

Multifunctional Opioid Ligands

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