Design and synthesis of a metabolically stable and potent antitussive agent, a novel δ opioid receptor antagonist, TRK-851

Sakami, Satoshi; Kawai, Koji; Maeda, Masayuki; Aoki, Toyohiro; Fujii, H.; Ohno, Hiroshi; Ito, Tsuyoshi; Saitoh, Akiyoshi; Nakao, Kaoru; Izumimoto, Naoki; Matsuura, Hirotoshi; Endo, Takashi; Ueno, Shinji; Natsume, Kazuto; Nagase, Hiroshi

doi:10.1016/j.bmc.2008.07.065

Cited by 25 publications

(13 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NTI derivative 9R,13S,2,quinolino [29,19:6,7]morphinan-14-ol(1b) methanesulfonate] showed moderate DOPr binding affinity and DOPr partial agonist activity (Sakami et al, 2008b). A TRK-850 analog, TRK-851 [(5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-89-fluoro-59,69-dihydro-49H-pyrrolo[3,2,1-ij]quinolino [29,19:6,7]morphinan-3,14-diol(1c) methanesulfonate], also showed DOPr antagonist properties and was metabolically more stable (Sakami et al, 2008a). Both compounds were shown to be orally active antitussive agents.…”

Section: B D-opioid Receptor Antagonistsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

View full text Add to dashboard Cite

Section: B D-opioid Receptor Antagonistsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

View full text Add to dashboard Cite

“…Moreover, benzoxazines were useful compounds as starting materials for the synthesis of larger structures with valuable biological activities [4][5][6]. N-Dichloroacetylb enzoxazines were used as herbicide safeners [7,8].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of N-dichloroacetyl-3-methyl-6,8-dichloro-3,4-dihydro- 2H-1,4-benzoxazine, C11H9Cl4NO2

Cheng

2014

Zeitschrift Für Kristallographie - New Crystal Structures

View full text Add to dashboard Cite

C 11 H 9 Cl 4 NO 2 ,monoclinic, P2 1 /c (no.14), a =11.995(2) Å, b =11.831(2)Å,c=9.798(2) Å, b =108.65(3)°, V =1317.5Å 3 ,Z=4,R gt (F) =0.0374, wR ref (F 2 ) =0.1050, T =293 K. Source of materialDichloroacetyl chloride (17.6m mol) wasa dded slowly in the mixture containing 3-methyl-6,8-dichloro-3,4-dihydro-2H-1,4-benzoxazine (14 mmol), Na 2 CO 3 (15.2 mmol), and benzene (25 mL). Thesystem was stirred at room temperature for 2h and TLC monitored. Then the mixture was rinsed, and the organic phase was dried over anhydrous magnesium sulfate. Benzene was removed under vacuum.The crude product was collected as white solid in 48% yield, and recrystallized from ethanol and light petroleum. Experimental detailsThe C-H atomswere then constrained to an ideal geometry, with C-H distances of 0.93-0.98 Å. The U iso values of the hydrogen atomsofmethyl groups were set to 1.5U eq (C methyl )and the U iso values of all other hydrogen atomswere set to 1.2U eq (C). DiscussionBenzoxazinederivatives have attracted widespread attention due to theirbroad applicationsinagriculture[1-3]. Moreover, benzoxazines were useful compounds as starting materials for the synthesis of larger structures with valuable biological activities [4][5][6]. N-Dichloroacetylb enzoxazines were used as herbicide safeners [7,8]. This contribution is acontinuation of our work to prepare and characterize N-dichloroacetyl-3-methyl-3,4-dihydro-1,4-benzoxazine through O-alkylation, reduction, cyclization and acylation reactions [9]. Thetitle molecule is composedoftwo planarrings,and it is obviousthatbenzene planeand oxazineringplane were almost in the sameplane with dihedral angle of 9.32(6)°. The torsion angles of N1-C7-C8-N2 was 60.3(2)°, showing ahalf-chair conformation. Obviously there is a large conjunctive effect between O1, benzene ring, N1, C9-O2 [C=O], which resulted in the shorter bond length than the typical C-N bond length and C-O bond length. In the crystal, molecules ares tablized by weak C-H×××Oh ydrogen bonds and van der Waals forces.

show abstract

“…ALD5859 and ALD5747 have completed phase II clinical trials for the treatment of ostheoarthritic knee pain, post-herpetic neuralgia and acute dental pain after third molar extraction, but failed to show significant effects to warrant further clinical investigations. TRK-851 may be close to entering clinical trials for the treatment of persistent cough (Nagase and Fujii 2011; Sakami et al 2008a). …”

Section: Future Prospects For the Development Of Dor Selective Drumentioning

confidence: 99%

“…And while the non-subtype-selective DOR antagonist NTI functioned as antitussive (Kamei et al 1993a), this may rather be caused by its effects on KOR at high enough concentrations. To avoid any off target effects, antagonists with improved selectivity for DOR over KOR and MOR have been developed and these drugs: TRK-850 [(5 R ,9 R ,13 S ,14 S )-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5′,6′-dihydro-3-methoxy-4′ H -pyrrolo[3,2,1- ij ]quinolino[2′,1′:6,7]morphinan-14-ol methanesulfonate] (Sakami et al 2008b), and the more metabolically stable TRK-851 (Sakami et al 2008a) show strong antitussive effects. Being antagonists, side effects such as respiratory depression and dependence may be less of an issue with these drugs.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

2013

View full text Add to dashboard Cite

Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders, and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR selective drugs are in clinical trials, but no DOR selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. This review will discuss the existing literature focusing on four aspects: 1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands 2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. 3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. 4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. These combined features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands.

show abstract

Design and synthesis of a metabolically stable and potent antitussive agent, a novel δ opioid receptor antagonist, TRK-851

Cited by 25 publications

References 29 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

Crystal structure of N-dichloroacetyl-3-methyl-6,8-dichloro-3,4-dihydro- 2H-1,4-benzoxazine, C11H9Cl4NO2

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

Contact Info

Product

Resources

About