10-Hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives (homobenzomorphans) as analgesics

Shiotani, Shunsaku; Kometani, Tadashi; Mitsuhashi, Kemmotsu; Nozawa, Tsutomu; Kurobe, Akira; Futsukaichi, Osamu

doi:10.1021/jm00228a013

Cited by 42 publications

(20 citation statements)

References 2 publications

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“…For the wide variety of modified benzomorphanes synthesized (2), all compounds were shown to be active (2, 3) at various levels, regardless of the nitrogen atom position and hence lone pair orientation. Although a "black or white" answer was not observed, minor structural variations in benzomorphan opiates have been associated with drastic changes in the relative agonist or antagonist properties (14).…”

Section: Discussionmentioning

confidence: 99%

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Molecular structure of opiate alkaloids. Part II. Crystal structures of 4-methylhomobenzomorphan hydrobromide (I)and 4,12β-dimethylhomobenzomorphan (II)

Michel¹,

Evrard²,

Norberg³

et al. 1988

Can. J. Chem.

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The two title compounds belong to the family homobenzomorphans. Their analgesic properties are comparable to morphine but without inducing physical dependence. This work presents the results of X-ray diffraction and NMR studies to elucidate the conformational properties particular to this class of compounds. More specifically, the spatial orientation of the nitrogen lone-pair are compared to those observed for other related molecules. The two molecules adopt the same L-shaped structure and the 16P-methyl substituent present in the second molecule does not modify this structure. Although very different in both structures, the intermolecular interactions do not alter the molecular conformation. The nitrogen lone pair is oriented away from the benzene ring and its orientation is conserved in solution, as proven by nrnr studies. The main conclusions are that the seven-membered ring shows very specific conformational properties and that the lone-pair orientation is predictable, according to the position of the nitrogen in the ring. Finally, it is concluded that correlations between the nitrogen lone-pair orientation and the analgesic activity have to be reconsidered. ANDRO G. MICHEL, GUY EVRARD, BERNADETTE NORBERG et E U G~N EMILCHERT. Can. J. Chem. 66, 1763 (1988). Les deux composts faisant l'objet de cette Ctude, appartiennent i la famille des homobenzomorphanes. Leurs proprittts analgtsiques se sont avtrtes trks inttressantes sous deux aspects: ils conservent une activitt proche de la morphine et d'autre part ne provoquent pas de dtpendance physique. Le prtsent travail vise i mettre en tvidence les proprittts conformatio~elles caracttristiques de ces composts, en vue d'en expliquer les proprittts typiques en terme de conformations. Plus particulikrement, I'orientation de la paire libre de I'azote est comparte 21 celle que l'on observe dans d'autres composCs analgksiques. I1 apparait que les deux moltcules adoptent la forme en L caracttristique et que le groupe 16P-mCthyl present dans le compost 11, n'induit aucune modification conformationnelle importante. Les interactions intermoltculaires sont tgalement dtcrites; quoique trks difftrentes d'une moltcule i I'autre, elles n'induisent pas non plus de modification conformationnelle notoire. Le comportement de ces moltcules en solution est aussi Ctudit. I1 s'avkre que ce type de moltcule posstdant un cycle C i 7 membres oriente la paire libre de l'azote de f a~o n sptcifique selon la position de l'atome d'azote dans le cycle. On doit tgalement conclure que la corrilation entre cette orientation et I'activitt analgtsique de ces moltcules doit &tre reconsidtrte. IntroductionThe present work is part of a more general crystal and molecular structure study of opiate alkaloids. The first part was published earlier (1) and reported oripavine and thebaine structure determinations in order to analyse the geometrical properties of narcotic opioids; the influence of the 16P-aryl substitution adjacent to the N atom in the piperidinyl ring was also discussed.The present paper deal...

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Section: Discussionmentioning

confidence: 99%

“…These compounds have been found to be very active as opioids: analgesic activity of title compounds were determined using optically resolved stereoisomers (2,3). Surprisingly, it was reported that the optical resolution gave no effect on the analgesic activity of compound I.…”

Section: Introductionmentioning

confidence: 99%

Molecular structure of opiate alkaloids. Part II. Crystal structures of 4-methylhomobenzomorphan hydrobromide (I)and 4,12β-dimethylhomobenzomorphan (II)

Michel¹,

Evrard²,

Norberg³

et al. 1988

Can. J. Chem.

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“…Indeed we found that the rigid tyramine constraint described above redirects the polypeptide backbones away from the PEO contour analogous to Class I superposition with the added effect that the Phe 4 aromatic ring fell outside of the vector map for the C21 ring of PEO. A tyramine conformation different from rigid alkaloids is also justified on other grounds: for example: (1) the synthetic hybrids of enkephalinamide and metazocine, sharing in common the tyramine moiety, have been shown to be inactive [50], and (2) the nitrogen locus, which is variable in analgesics [51][52][53], could also be different in these opioid peptides and, by extension, would not manifest parallel structure-activity relationships as rigid alkaloids [54]. Indeed the model proposed by Portoghese et al [53] reconciles some of these apparent anomalies.…”

Section: Comparison With Other Receptor Modelsmentioning

confidence: 99%

A proposal for the molecular basis of ? and ? opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid

Michel

Villeneuve

DiMaio

1991

J Computer-Aided Mol Des

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The molecular basis underlying the divergent receptor selectivity of two cyclic opioid peptides Tyr-c[N delta-D-Orn2-Gly-Phe-Leu-] (c-ORN) and [D-Pen2,L-Cys5]-enkephalinamide (c-PEN) was investigated using a molecular modeling approach. Ring closure and conformational searching procedures were used to determine low-energy cyclic backbone conformers. Following reinsertion of amino acid side chains, the narcotic alkaloid 7 alpha-[(1R)-1-methyl-1-hydroxy-3-phenylpropyl]-6-14-endoethenotetrahy dro oripavine (PEO) was used as a flexible template for bimolecular superpositions with each of the determined peptide ring conformers using the coplanarity and cocentricity of the phenolic rings as the minimum constraint. A vector space of PEO, accounting for all possible orientations for the C21-aromatic ring of PEO served as a geometrical locus for the aromatic ring of the Phe4 residue in the opioid peptides. Although a vast number of polypeptide conformations satisfied the criteria of the opiate pharmacophore, they could be grouped into three classes differing in magnitude and sign of the torsional angle values of the tyrosyl side chain. Only class III conformers for both c-ORN and c-PEN, having tyramine dihedral angles chi 1 = 150 degrees +/- 30 degrees and chi 2 = -155 degrees +/- 20 degrees, had significant structural and conformational properties that were mutually compatible while respecting the PEO vector space. Comparison of these properties in the context of the divergent receptor selectivity of the studied opioid peptides suggests that the increased distortion of the peptide backbone in the closure region of c-PEN together with the pendant beta,beta-dimethyl group, combine to generate a steric volume which is absent in c-ORN and that may be incompatible with a restrictive topography of the mu receptor. The nature and stereochemistry of substituents adjacent to the closure region of the peptides could also modulate receptor selection by interacting with a charged (delta) or neutral (mu) subsite.

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“…The racemate and isomer were prepared as described in the literature (23)(24)(25). The method of preparation and optical rotation and melting points of the enantiomers leave no doubt about their optical purity.…”

Section: Drugsmentioning

confidence: 99%

Pharmacological Actions of the Racemic and the Enantiomeric 1,4-Dimethyl-IO-Hydroxy-2,3,4,5,6,7-Hexahydro-1,6-Methano-IH-4-Benzazonines (C-Homobenzomorphans)

Aceto

Harris

Woods

et al. 1985

Japanese Journal of Pharmacology

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Abstract-The racemate and optical isomers of the C-homobenzomorphans, 1,4 -dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine, were evaluated in a number of assays sensitive to narcotics of different types.All three C-homobenzomorphans were active in vitro in guinea pig ileum, mouse vas deferens, and rat brain membrane binding assays, but were of low potency. These C-homobenzomorphans showed different profiles of in vivo activity. The (+)-isomer and racemate were active as agonists in the tail-flick assay, whereas the (-)-isomer was inactive. At higher doses, the (-)-isomer and the racemate behaved as antagonists of morphine in the tail-flick assay. All three compounds were active in the phenylquinone test, but naloxone did not block this effect . In addition, all three were potent in the hot-plate test. Neither of the isomers sub stituted for morphine in dependent rats or monkeys. However, the (+)-isomer precipitated withdrawal in these monkeys.The (-)-isomer produced opioid-like physical dependence in both rats and monkeys.Some of the implications regarding the results with these remarkable homobenzomorphans are discussed.

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10-Hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives (homobenzomorphans) as analgesics

Cited by 42 publications

References 2 publications

Molecular structure of opiate alkaloids. Part II. Crystal structures of 4-methylhomobenzomorphan hydrobromide (I)and 4,12β-dimethylhomobenzomorphan (II)

Molecular structure of opiate alkaloids. Part II. Crystal structures of 4-methylhomobenzomorphan hydrobromide (I)and 4,12β-dimethylhomobenzomorphan (II)

A proposal for the molecular basis of ? and ? opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid

Pharmacological Actions of the Racemic and the Enantiomeric 1,4-Dimethyl-IO-Hydroxy-2,3,4,5,6,7-Hexahydro-1,6-Methano-IH-4-Benzazonines (C-Homobenzomorphans)

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