Morphinans - Potent - Euphoria Without Addiction?

scarmani · Mon Apr 25, 2005 4:49 am

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon: An Extremely Powerful Analgesic
Johannes Schutz, Mariana Spetea, Martin Koch, Mario D. Aceto, Louis S. Harris, Andrew Coop, and Helmut Schmidhammer,
J. Med. Chem. 46(19), pp. 4182-4187 (2003)
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Abstract:
The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors (mu, kappa, delta), with 14- henylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-ethoxymetopon (1).

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Identification of Opioid Ligands Possessing Mixed mu-Agonist/delta-Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydropmorphone
Subramaniam Ananthan, Naveen K. Khare, Surendra K. Saini, Lainne E. Seitz, Jeffrey L. Bartlett, Peg Davis, Christina M. Dersch, Frank Porreca, Richard B. Rothman, and Edward J. Bilsky,
J. Med. Chem. 47(6), pp. 1400-1412 (2004)
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Abstract:
A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid delta, mu, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [35S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the mu and delta receptors. Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the mu and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the mu site. Nearly all of the ligands possessing an N-methyl group at the 17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the mu receptor with varying potencies and efficacies. In the [35S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed mu agonist / delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard mu agonist morphine produces significant tolerance, repeated administration of the mu agonist / delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed mu agonist / delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.

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Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22.1 Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities
Roberta Lattanzi, Mariana Spetea, Falko Schüllner, Silvia B. Rief, Roland Krassnig, Lucia Negri, and Helmut Schmidhammer,
J. Med. Chem. 48(9), pp. 3372 -3378 (2005)
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Abstract:

Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid binding affinity was sensitive to the character and length of the substituent in position 14. In smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound 7 showed negligible constipating activity at the analgesic dose. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no significant effect on in vitro biological activities, but resulted in decreased antinociceptive potency.

scarmani · Mon May 02, 2005 1:03 pm

here are journal articles about benzomorphans from J. Med Chem

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New Benzomorphan Analgetics
Maxwell Gordon, John J. Lafferty, David H. Tedeschi, Blaine M. Sutton, Nathan B. Eddy, Everett L. May;,
J. Med. Chem.; 1962; 5(3); 633-635.
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Acyl derivatives of 5-hydroxy-6,7-benzomorphans. Prodine congeners
Mikio Takeda, Everette L. May;,
J. Med. Chem.; 1970; 13(6); 1223-1224.
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Interesting Pharmacological Properties of the Optical Isomers of -5,9-Diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan
Everette L. May, Nathan B. Eddy;,
J. Med. Chem.; 1966; 9(6); 851-852.
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Homologs of benzomorphan derivatives. 1
Mikio Takeda, Hiroshi Kugita;,
J. Med. Chem.; 1970; 13(4); 630-634.
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Absolute configuration of some benzomorphan analgetics and related compounds
Alan F. Casy, Anilkumar P. Parulkar;,
J. Med. Chem.; 1969; 12(1); 178-180.
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N-(2-Cyanoethyl) derivatives of meperidine, ketobemidone, and a potent 6,7-benzomorphan
Ibrahim M. Uwaydah, M. Kathleen Waddle, Michael E. Rogers;,
J. Med. Chem.; 1979; 22(7); 889-890.
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Synthesis and analgetic activity of the diastereomeric 8-hydroxy-6,7-benzomorphans
Jon J. Fauley, Jules B. LaPidus;,
J. Med. Chem.; 1973; 16(2); 181-182.
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Structures Related to Morphine. XXV. 5-Propyl- and 5,9-Dipropyl-6,7-benzomorphans and a Pharmacologic Summary
J. Harrison Ager, S. E. Fullerton, Everette L. May;,
J. Med. Chem.; 1963; 6(3); 322-325.
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Structures Related to Morphine. XXXII.1 - and -2,9-Dimethyl-5-propyl-6,7-benzomorphan from 3-Methyl-4-propylpyridine
Bhuwan C. Joshi, Everette L. May;,
J. Med. Chem.; 1965; 8(5); 696-697.
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Structures Related to Morphine. XXX.1 N-Hexyl- and 5-Butyl-, -Amyl-, and -Hexyl-6,7-benzomorphans
Bhuwan C. Joshi, Colin F. Chignell, Everette L. May;,
J. Med. Chem.; 1965; 8(5); 694-696.
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Structures Related to Morphine. XXII.1 A Benzomorphan Congener of Meperidine
Hiroshi Kugita, Seiichi Saito, Everette L. May;,
J. Med. Chem.; 1962; 5(2); 357-361.
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Benzomorphans. Optically Active and trans Isomers
B. F. Tullar, L. S. Harris, R. L. Perry, Anne K. Pierson, A. E. Soria, W. F. Wetterau, N. F. Albertson;,
J. Med. Chem.; 1967; 10(3); 383-386.
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3'-Methyl, 8-methyl, and 8-phenyl derivatives of 5,9-dimethyl-6,7-benzomorphans
Albert Ziering, Nicholas Malatestinic, Thomas Williams, Arnold Brossi;,
J. Med. Chem.; 1970; 13(1); 9-13.
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Structures Related to Morphine. XXXI.1 2'-Substituted Benzomorphans
Arthur E. Jacobson, Everette L. May;,
J. Med. Chem.; 1965; 8(5); 563-566.
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Synthesis and in Vitro and in Vivo Activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-Alkenyl-, -N-Alkynyl-, and -N-Cyanoalkyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan Homologues
May, E. L.; Jacobson, A. E.; Mattson, M. V.; Traynor, J. R.; Woods, J. H.; Harris, L. S.; Bowman, E. R.; Aceto, M. D.;,
J. Med. Chem.; (Article); 2000; 43(26); 5030-5036.
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Optical resolution of (+-)-2,5-dimethyl-2'-hydroxy-9.alpha.- and -9.beta.-propyl-6,7-benzomorphans and their pharmacological properties
Kenner C. Rice, Arthur E. Jacobson;,
J. Med. Chem.; 1976; 19(3); 430-432.
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Effect of 9-hydroxylation on benzomorphan antagonist activity
Noel F. Albertson;,
J. Med. Chem.; 1975; 18(6); 619-621.
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Synthesis of 6,7-benzomorphan and related nonquaternary carbon structures with marked analgetic activity
Ken Kanematsu, Mikio Takeda, Arthur E. Jacobson, Everette L. May;,
J. Med. Chem.; 1969; 12(3); 405-408.
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Benzomorphans. Structure of a position isomer
N. F. Albertson, W. F. Michne, B. F. Tullar;,
J. Med. Chem.; 1978; 21(5); 471-474.
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Synthesis and Opioid Receptor Affinity of Morphinan and Benzomorphan Derivatives: Mixed k Agonists and m Agonists/Antagonists as Potential Pharmacotherapeutics for Cocaine Dependence
Neumeyer, J. L.; Bidlack, J. M.; Zong, R.; Bakthavachalam, V.; Gao, P.; Cohen, D. J.; Negus, S. S.; Mello, N. K.;,
J. Med. Chem.; (Article); 2000; 43(1); 114-122.
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Synthesis and pharmacological activity of some N-alkyl-substituted 9.alpha.-ethyl-2'-hydroxy-5-methyl-6,7-benzomorphans
Ibrahim M. Uwaydah, Everette L. May, Louis S. Harris;,
J. Med. Chem.; 1977; 20(11); 1374-1377.
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Synthesis and analgetic activity of 3- and 4-methyl-6,7-benzomorphans
Robert T. Parfitt, Susan M. Walters;,
J. Med. Chem.; 1971; 14(7); 565-568.
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Synthesis and pharmacology of 2,9.alpha.-dimethyl-2'-hydroxy-6,7-benzomorphan
Hirozumi Inoue, Everette L. May;,
J. Med. Chem.; 1976; 19(2); 259-262.
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Structures Related to Morphine. XXVII.1 - and -5,9-Diethyl-2-methyl-6,7-benzomorphans
Arthur E. Jacobson, Everette L. May;,
J. Med. Chem.; 1964; 7(4); 409-412.
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Analgesics and narcotic antagonists in the benzomorphan and 8-oxamorphinan series. 5
Yvon Lambert, Jean Paul Daris, Ivo Monkovic, Anthony W. Pircio;,
J. Med. Chem.; 1978; 21(5); 423-427.
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Synthesis and analgesic activities of 2,5-dimethyl-2'-hydroxy-9.alpha.- and -.beta.-propyl-6,7-benzomorphans
Kenner C. Rice, Arthur E. Jacobson, Everette L. May;,
J. Med. Chem.; 1975; 18(8 ); 854-857.
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Constitution and Analgetic Activity of a New Product in the Benzomorphan Synthesis
Bhuwan C. Joshi, Everette L. May, H. M. Fales, J. W. Daly, A. E. Jacobson;,
J. Med. Chem.; 1965; 8(5); 559-563.
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Structures Related to Morphine. XXVIII.1 Alternative Syntheses of - and -2,9-Dimethyl-2'-hydroxy-5-propyl-6,7-benzomorphan
Colin F. Chignell, J. Harrison Ager, Everette L. May;,
J. Med. Chem.; 1965; 8(2); 235-238
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Pentazocine.1 Strong Analgesics and Analgesic Antagonists in the Benzomorphan Series
S. Archer, N. F. Albertson, L. S. Harris, Anne K. Pierson, J. G. Bird;,
J. Med. Chem.; 1964; 7(2); 123-127.
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Asymmetric Synthesis of 9-Alkyl-2-benzyl-6,7-benzomorphans: Characterization as Novel Receptor Ligands
Carroll, F. I.; Bai, X.; Dehghani, A.; Mascarella, S. W.; Williams, W.; Bowen, W. D.;,
J. Med. Chem.; (Article); 1999; 42(22); 4621-4629.
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5-Allyl-9-oxobenzomorphans. 3. Potent narcotic antagonists and analgesics-antagonists in the series of substituted 2',9.beta.-dihydroxy-6,7-benzomorphans
Michel Saucier, Jean Paul Daris, Yvon Lambert, Ivo Monkovic, Anthony W. Pircio;,
J. Med. Chem.; 1977; 20(5); 676-682.
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Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with nonmorphinelike action profiles
Herbert Merz, Klaus Stockhaus, Helmut Wick;,
J. Med. Chem.; 1975; 18(10); 996-1000.
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Synthesis and .sigma. Binding Properties of 2'-Substituted 5,9.alpha.-Dimethyl-6,7-benzomorphans
Richmond Danso-Danquah, Xu Bai, X. Zhang, S. Wayne Mascarella, Wanda Williams, Bethel Sine, Wayne D. Bowen, F. Ivy Carroll;,
J. Med. Chem.; 1995; 38(15); 2978-2985.
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Synthesis and analgetic activity of some benzomorphan analogs
Tadashi Kometani, Shunsaku Shiotani;,
J. Med. Chem.; 1978; 21(11); 1105-1110.
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Conformation of 2,9-dimethyl-3'-hydroxy-5-phenyl-6,7-benzomorphan and its relation to other analgetics and enkephalin
Frank H. Clarke, Hermann Jaggi, Richard A. Lovell;,
J. Med. Chem.; 1978; 21(7); 600-606.
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Synthesis and Structure-Activity Relationships of 6,7-Benzomorphan Derivatives as Antagonists of the NMDA Receptor-Channel Complex
Grauert, M.; Bechtel, W. D.; Ensinger, H. A.; Merz, H.; Carter, A. J.;,
J. Med. Chem.; (Article); 1997; 40(1; 2922-2930.
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Antipodal .alpha.-N-(Methyl through Decyl)-N-normetazocines (5,9.alpha.-Dimethyl-2'-hydroxy-6,7-benzomorphans): In vitro and In vivo Properties
Everette L. May, Mario D. Aceto, Edward R. Bowman, Christine Bentley, Billy R. Martin, Louis S. Harris, Fedor Medzihradsky, Mariena V. Mattson, Arthur E. Jacobson;,
J. Med. Chem.; 1994; 37(20); 3408-3418.
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Syntheses, analgetic activity and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives
Naokata Yokoyama, Prabodh I. Almaula, Fred B. Block, Frank R. Granat, Norman Gottfried, Ronald T. Hill, Elihu H. McMahon, Walter F. Munch, Howard Rachlin, et al.;,
J. Med. Chem.; 1979; 22(5); 537-553.
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Synthesis of pentazocine
Noel F. Albertson, William F. Wetterau;,
J. Med. Chem.; 1970; 13(2); 302-303.
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scarmani · Thu May 12, 2005 11:59 am

here are articles about benzomorphans from J. Org. Chem and J. Am. Chem. Soc.

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Structures Related to Morphine. IX. Extension of the Grewe Morphinan Synthesis in the Benzomorphan Series and Pharmacology of Some Benzomorphans
Nathan B. Eddy, James G. Murphy, Everette L. May;
J. Org. Chem.; 1957; 22(11); 1370-1372.
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Synthesis of 6,7-benzomorphan from 4-phenylpyridine
Ken Kanematsu, Robert T. Parfitt, Arthur E. Jacobson, J. Harrison Ager, Everette L. May;
J. Am. Chem. Soc.; 1968; 90(4); 1064-1065.
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Rearrangement Products of 9-Acetoxy- and 9-Hydroxy-2,5,9-trimethyl-6,7-benzomorphans
Robert T. Parfitt, E. M. Fry, Everette L. May;
J. Org. Chem.; 1966; 31(3); 903-905.
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Synthesis of Analgesics with Benzomorphane Structure. A Possible Intermediate: 1-Methyl-2-benzyl-4-piperidol
U. M. Teotino;
J. Org. Chem.; 1962; 27(5); 1906-1908.
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Structures Related to Morphine. XXI. An Alternative Synthesis of Diastereoisomeric 2'-Hydroxy-2,5,9-trimethyl-6,7-benzomorphans
Seiichi Saito, Everette L. May;
J. Org. Chem.; 1962; 27(3); 1087-1089.
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Structures Related to Morphine. XIX. Benzomorphans from 3,4-Diethylpyridine
J. Harrison Ager, Everette L. May;
J. Org. Chem.; 1962; 27(1); 245-247.
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Structures Related to Morphine. XII. (±)-2'-Hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan (NIH 7519) and Its Optical Forms
Everette L. May, Nathan B. Eddy;
J. Org. Chem.; 1959; 24(10); 1435-1437.
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Structures Related to Morphine. XIII. 2-Alkyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphans and a More Direct Synthesis of the 2-Phenethyl Compound (NIH 7519)
J. Harrison Ager, Everette L. May;
J. Org. Chem.; 1960; 25(6); 984-986.
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Improved synthesis of a 9-oxo-6,7-benzomorphan and its homolog. Novel rearrangement of heterocyclic enamines via bromination
Mikio Takeda, Hirozumi Inoue, Mikihiko Konda, Seiichi Saito, Hiroshi Kugita;
J. Org. Chem.; 1972; 37(17); 2677-2679.
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Structures Related to Morphine. XIV. 2'-Hydroxy-5-methyl-2-phenethyl-6,7-benzomorphan, the 9-Demethyl Analog of NIH 7519 (Phenazocine) from 3,4-Dihydro-7-methoxy-2(1H)naphthalenone
James G. Murphy, J. Harrison Ager, Everette L. May;
J. Org. Chem.; 1960; 25(8 ); 1386-1388.
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Structures Related to Morphine. VIII. Further Syntheses in the Benzomorphan Series
Everette L. May, Edward M. Fry;
J. Org. Chem.; 1957; 22(11); 1366-1369.
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Synthesis of 2,9.beta.-dimethyl-6,7-benzomorphan
Tokuro Ohishi, Arthur E. Jacobson, Raymond S. Wilson, Herman J. C. Yeh, Everette L. May;
J. Org. Chem.; 1974; 39(10); 1347-1349.
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Structures Related to Morphine. XI. Analogs and a Diastereoisomer of 2'-Hydroxy-2,5,9-trimethyl-6,7-benzomorphan
Everette L. May, J. Harrison Ager;
J. Org. Chem.; 1959; 24(10); 1432-1435.
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Structure Related to Morphine. XXVI. Cyclization Experiments with 2-Benzyl-1,3,4-trialkyl-1,2,5,6-tetrahydropyridines. Improved Yields of -5,9-Dialkyl-6,7-benzomorphans
J. Harrison Ager, S. E. Fullerton, E. M. Fry, Everette L. May;
J. Org. Chem.; 1963; 28(9); 2470-2472.
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Structures Related to Morphine. XXIII. Stereochemistry of 5,9-Dialkyl-6,7-benzomorphans
S. Edward Fullerton, Everette L. May, Edwin D. Becker;
J. Org. Chem.; 1962; 27(6); 2144-2147.
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Structures Related to Morphine. XX. Stevens Reaction in the Synthesis of 5-Ethyl-2'-hydroxy-2-methyl-(or phenethyl)-6,7-benzomorphan
Seiichi Saito, Everette L. May;
J. Org. Chem.; 1962; 27(3); 948-951.
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Structures Related to Morphine. XXIV. Further Application of the Stevens Rearrangement in the Synthesis of Diastereoisomeric 6,7-Benzomorphans from 3-Ethyl-4-methyl- and 4-Ethyl-3-methylpyridines
S. E. Fullerton, J. H. Ager, E. L. May;
J. Org. Chem.; 1962; 27(7); 2554-2557.
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New Benzomorphan Ring Closure in the Synthesis of 5-Phenylbenzomorphans
Gordon N. Walker, David Alkalay;
J. Org. Chem.; 1966; 31(6); 1905-1911.
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Meta bridging reactions of electron-deficient aromatics. I. One-step synthesis of the 6,7-benzomorphan ring system. Facile preparation of potential narcotic antagonists
Raymond R. Bard, Michael J. Strauss;
J. Am. Chem. Soc.; 1975; 97(13); 3789
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6,7-Benzomorphans. Stereospecific synthesis of 2,9.alpha.- and 2,9.beta.-dimethyl-2'-methoxy-6,7-benzomorphans
Richard D. Gless, Henry Rapoport;
J. Org. Chem.; 1979; 44(8 ); 1324-1336.
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Benzomorphans: synthesis, stereochemistry reactions, and spectroscopic characterizations
David C. Palmer, Michael J. Strauss;
Chem. Rev.; 1977; 77(1); 1-36.
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A novel cleavage of aryl benzyl ethers and allyl aryl ethers by sodium bis(2-methoxyethoxy)aluminum hydride. An alternative synthesis of pentazocine
Tetsuji Kametani, Shyh-Pyng Huang, Masataka Ihara, Keiichiro Fukumoto;
J. Org. Chem.; 1976; 41(15); 2545-2548.
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Studies on the synthesis of heterocyclic compounds. 726. Thermal rearrangement of aminomethyl cyclopropyl ketones and a novel synthesis of pentazocine
Tetsuji Kametani, Hideharu Seto, Hideo Nemoto, Keiichiro Fukumoto;
J. Org. Chem.; 1977; 42(22); 3605-3608.
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Guest · Sat May 14, 2005 5:01 pm

What about Tramadol, that fits all the above,

Whether or not the real studies have shown addiction is only speculation to me at the moment, but I would hope to think so,

Syn

Star-light · Blacklight bulb

Tramadol does not seem to create euporia or pronounced opiate like effects in most individuals. However I do find it makes me a bit more relaxed and happier.

stooge · Mon May 23, 2005 2:07 am

in amounts high enough it helps against withdrawal. In even higher amounts
it produces a rather "rushy", un-clean feeling, somehow low-quality buzz ...
but, well, better than nothing Smile

Tilidine, for example, is much nicer. no clue, is that a morphinan, too?

kingofpeace · Wed May 25, 2005 1:57 pm

Now let me get this straight, science is FINALLY coming far enough to come up with something that doesnt cause the WD's? This would be an incredible breakthrough especially for those people I take care of who are hooked on the MS-Contins that they are prescribed.

I read last night somewhere that you can only take as low as 16mg daily doses of morphine, and quit cold turkey, without fear of death. And that is nearly the lowest dose of mscontin provided on the market today. But wouldnt this wipe out the morphine industry, I mean, I know alot of ppl who have choosen to live with the pain rather that the addiction of morphine. So all of them would try this new non-addictive morphine supplement.

Most of the ppl I take care of take their mscontin thru iv use, and the WD's I have had to witness were simply horrible beyond anything I can describe in words here. It would be great to have something like this come about at a time where the FDA has approved Palladone (4 times stronger than Dilaudid/Hydromorphone) which will be the next great hallocaust in America. Palladone is scheduled to hit the markets this spring and will surely rival oxy and mscontins in deaths.

Whoever found this information, this subject needs to be highlighted somewhere on this forum if it isnt already because it could save many many lives. I have to order mscontin from overseas pharmacies when my patients run out of their meds early because tolerance to mscontin is everywhere. Most addicts turn to cocaine when they are out of their medicine where I am from, which is far from clean as morphine is, not to mention the risk they put themselves in purchasing a narcotic like that.

Whoever has discovered this morphine supplement free of the addictive qualities should indeed be given the Noble Prize without a doubt.