Mild, Pd-catalyzed stannylation of radioiodination targets

Pickett, Julie E.; Váradi, András; Palmer, Travis C.; Grinnell, Steven G.; Schrock, Joel M.; Pasternak, Gavril W.; Karimov, Rashad R.; Majumdar, Susruta

doi:10.1016/j.bmcl.2015.02.055

Cited by 14 publications

(14 citation statements)

References 30 publications

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“…IBNtxA and [ 125 I]BNtxA were synthesized in our laboratory as previously described. 78–80 Na 125 I and [ 35 S]GTP γ S were purchased from PerkinElmer (Waltham, MA). Selective opioid antagonists were purchased from Tocris Bioscience.…”

Section: Methodsmentioning

confidence: 99%

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Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

et al. 2016

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Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [35S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.

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Section: Methodsmentioning

confidence: 99%

“…7–9,80 Binding was performed at 25 °C for 90 min. Binding in MOR-1/CHO was carried out in 50 mM potassium phosphate buffer with 5 mM MgSO 4 and 20 μ g/mL protein, while binding in KOR-1/CHO and DOR-1/CHO was carried out in 50 mM potassium phosphate pH = 7.0 buffer and 40 μ g/mL protein.…”

Section: Methodsmentioning

confidence: 99%

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

et al. 2016

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“…IBNtxA , MP1104, MP102 and new compounds ( MP1202 , MP1207-MP12108 , MP1305 , and MP1601 ) were synthesized. [ 125 I]BNtxA was prepared as previously described ( Pickett et al, 2015 ). Reagents Na 125 I and [ 35 S]GTPγS were purchased from Perkin-Elmer (Waltham, MA).…”

Section: Methodsmentioning

confidence: 99%

“…[ 125 I]IBNtxA binding was carried out in membranes prepared from Chinese Hamster Ovary (CHO) cells stably expressing murine clones of mMOR, mDOR, and mKOR, as previously described ( Váradi et al, 2015a ; Pickett et al, 2015 ; Váradi et al, 2013 ). In brief, binding was performed at 25°C for 90 min.…”

Section: Methodsmentioning

confidence: 99%

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Uprety

Che

Zaidi

et al. 2021

eLife

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Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

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“…IBNtxA and [ 125 I]BNtxA were synthesized in our laboratory as previously described. 9,17,37 Na 125 I and [ 35 S]GTP γ S were purchased from PerkinElmer. Miscellaneous chemicals and bufiers were purchased from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

Váradi

Marrone

Eans

et al. 2015

ACS Chem. Neurosci.

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3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-Hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.

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Mild, Pd-catalyzed stannylation of radioiodination targets

Cited by 14 publications

References 30 publications

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

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