Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans

Lemaire, Simon; Belleau, B.; Jolicoeur, F.B.

doi:10.1016/0014-2999(94)90063-9

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…They prepared and tested both axial and equatorial derivatives of sulforphanol ( 13 ) and sulfallorphan ( 14 ), finding that the sulfonium analogues retained potency. Furthermore, the agonist versus antagonist activity associated with these compounds was found to depend on the conformation of the S -substituent in agreement with Snyder’s proposal (equatorial allyl group confers antagonist activity, axial methyl confers agonist activity) …”

Section: Introductionsupporting

confidence: 87%

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Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

et al. 2013

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Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone.

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Section: Introductionsupporting

confidence: 87%

“…Furthermore, the agonist versus antagonist activity associated with these compounds was found to depend on the conformation of the S -substituent in agreement with Snyder’s proposal (equatorial allyl group confers antagonist activity, axial methyl confers agonist activity). 9 …”

Section: Introductionmentioning

confidence: 99%

Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

et al. 2013

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“…On the other hand, sulfonium analogues of levorphanol and levallorphan, in which the nitrogen atom of these alkaloids has been replaced by tertiary S -methyl and S -allyl groups, were found to retain significant potency. This result was interpreted to mean that a positively charged heteroatom, other than nitrogen, can also interact with an anionic site on opioid receptors and induce agonism . Ronai et al reported in 1992 that Boc-Tyr-Pro-Gly-Phe-Leu-Thr(OtBu)-OH, an opioid peptide lacking a positive charge, was a moderately potent δ-opioid antagonist in the mouse vas deferens (MVD) assay ( K e ≈ 30 nM) .…”

Section: The δ-Opioid Receptormentioning

confidence: 99%

Novel Ligands Lacking a Positive Charge for the δ- and μ-Opioid Receptors

et al. 2000

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Recently we reported using minilibraries to replace Lys(9) [somatostatin (SRIF) numbering] of the potent somatostatin agonist L-363,301 (c[-Pro-Phe-D-Trp-Lys-Thr-Phe-]) to generate the potent neurokinin receptor (NK-1) antagonist c[-Pro-Phe-D-Trp-p-F-Phe-Thr-Phe-]. This novel cyclic hexapeptide did not bind the SRIF receptor. Thus, a single mutation converted L-363,301, a SRIF agonist with potency ca. 2-8 times the potency of SRIF in laboratory animals,(24) into a selective NK-1 receptor antagonist with an IC(50) of 2 nM in vitro. During the screening of the same libraries for ligands of the delta-opioid receptor, we identified four compounds (1-4) which represent a new class of delta-opioid antagonists, some of which were also NK-1 receptor antagonists. The most potent delta-opioid antagonist, c[-Pro-1-Nal-D-Trp-Tyr-Thr-Phe-] (2), showed a K(e) value of 128 nM in the mouse vas deferens assay and a delta-receptor binding affinity constant of 152 nM in the rat brain membrane binding assay. These results are of interest because they represent a novel class of delta-opioid antagonists and, like two previously reported delta-opioid antagonists, they lack a positive charge. To examine further the requirement for a positive charge in the delta-opioid ligands, we prepared two analogues of the beta-casomorphin-derived mixed mu-agonist/delta-antagonist, H-Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-] (7), in which we eliminated the positive charge either through formylation of the primary amino group (5) or by the deletion of this N-terminal amino group (6). These latter compounds proved to be delta-opioid antagonists with K(e) values in the 16-120 nM range, as well as fairly potent mu-opioid antagonists (K(e) approximately 200 nM). These six compounds provide the most convincing evidence to date that there is no requirement for a positive charge in mu- and delta-opioid receptor antagonists. In addition, cyclic hexapeptide 4 lacks a phenolic hydroxyl group. Taken together, these data suggest that the prevailing assumptions about delta- and mu-opioid receptor binding need revision and that the receptors for these opioid ligands have much in common with the NK-1 and somatostatin receptors.

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“…Indeed, the agonist and antagonist activity was found to depend on the conformation of the S-substituent: the equatorial allyl group leads to antagonist activity and the axial methyl confers agonist activity. 16 To our knowledge, there were no other heteroatom analogues of morphinans reported in the literature.…”

Section: Heteroatom Analogues Of Hydrocodonementioning

confidence: 92%

Recent advances in process development for opiate-derived pharmaceutical agents

Hudlický

2015

Can. J. Chem.

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This short review summarizes our work on the process development for the synthesis of buprenorphine, naltrexone, naloxone, and nalbuphine from naturally occurring opiates such as thebaine and oripavine. Several new methods for N-demethylation of morphinans have been developed during the pursuit of this research. The article traces the evolution of various approaches and provides a comparison for overall efficiency.

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Agonist and antagonist opioid activity of axial and equatorial conformations of S-methyl- and S-allyl-morphinans

Cited by 6 publications

References 20 publications

Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

Novel Ligands Lacking a Positive Charge for the δ- and μ-Opioid Receptors

Recent advances in process development for opiate-derived pharmaceutical agents

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