The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

Wang, Meining; Irvin, Thomas C.; Herdman, Christine A.; Hanna, Ramsey D.; Hassan, Sergio A.; Lee, Yong‐Sok; Kaska, Sophia; Crowley, Rachel Saylor; Prisinzano, Thomas E.; Withey, Sarah L.; Paronis, Carol A.; Bergman, Jack; Inan, Saadet; Geller, Ellen B.; Adler, Martin W.; Kopajtic, Theresa; Katz, Jonathan L.; Chadderdon, Aaron M.; Traynor, John R.; Jacobson, Arthur E.; Rice, Kenner C.

doi:10.3390/molecules25112640

Cited by 11 publications

(12 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ventilation measures were assessed as described previously [ 25 ]. Briefly, squirrel monkeys were acclimated to a customized acrylic chamber (10″ d × 10″ w × 10″ h) that served as a whole-body plethysmograph (EMKA Technologies, Montreal, PQ, Canada).…”

Section: Methodsmentioning

confidence: 99%

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

show abstract

Section: Methodsmentioning

confidence: 99%

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, exchanging the N-methyl group by an N-phenethyl substituent in other opioid ligands, such as 5phenylmorphans, led to MOP antagonists [117,118]. A recent study reported on (-)-Nphenethyl analogs of N-norhydromorphone, with the N-p-chlorophenethylnorhydromor phone as a bifunctional MOP/DOP ligand with partial agonism at the MOP receptor and a full agonism at the DOP receptor, and antinociceptive efficacy without respiratory depression in squirrel monkeys after s.c. administration [119]. Remarkable SAR observations were made for N-methyl substituted 2 and 4 and their N-phenethyl substituted counterparts 2b and 4b, and also extended to the N-phenethyl analogues of morphine and oxymorphone, 22b and 1b, respectively (Figure 3) [94].…”

Section: Modifications In Position 17 Of N-methylmorphinan-6-ones: Design Synthesis and Sar Studiesmentioning

confidence: 82%

“…Furthermore, exchanging the N -methyl group by an N -phenethyl substituent in other opioid ligands, such as 5-phenylmorphans, led to MOP antagonists [ 117 , 118 ]. A recent study reported on (-)- N -phenethyl analogs of N -norhydromorphone, with the N - p -chlorophenethylnorhydromorphone as a bifunctional MOP/DOP ligand with partial agonism at the MOP receptor and a full agonism at the DOP receptor, and antinociceptive efficacy without respiratory depression in squirrel monkeys after s.c. administration [ 119 ].…”

Section: Modifications In Position 17 Of N -Methylmorphinan-6-ones: Design Synthesis and Sar Studiesmentioning

confidence: 99%

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Spetea

Schmidhammer

2021

Molecules

View full text Add to dashboard Cite

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

show abstract

“…The crude mixture was loaded onto silica and purified via flash chromatography eluting with 0-30% ethyl acetate in hexane to yield 17 as a yellow oil (3.39 g, 55%) [α] D 25 −33.8 • (c 1.4, CHCl 3 ). 1 H-NMR (400 MHz; CDCl 3 ): δ 7.30-7.26 (m, 1H), 6.81-6.77 (m, 3H), 4.39-4.09 (m, 2H), 3.80 (s, 3H), 3.21-3.14 (m, 1H), 2.65-2.48 (m, 2H), 2.39-2.27 (m, 2H), 2.23-2.14 (m, 2H), 1.80-1.64 (m, 2H), 1.49 (s, 9H); 13 (18). To dry tetrahydrofuran (10 mL) was added sodium hydride (275 mg, 60% weight, 3.0 equiv, 6.87 mmol), followed by slow addition of ethyl 2-(diethoxyphosphoryl)acetate (1.540 g, 1.36 mL, 3.0 equiv., 6.87 mmol).…”

Section: Synthesismentioning

confidence: 99%

Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans

et al. 2023

Self Cite

View full text Add to dashboard Cite

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.

show abstract

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

Cited by 11 publications

References 45 publications

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans

Contact Info

Product

Resources

About