Phenylmorphan agonists-antagonists

Hh, Ong; Oishi, Tetsuya; El, May

doi:10.1021/jm00247a026

Cited by 35 publications

(23 citation statements)

References 1 publication

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“…15 Furthermore, replacement of the N-methyl substituent with moieties known to confer narcotic antagonist activity in the 4,5-epoxymorphinans, such as propyl, allyl, and cyclopropylmethyl, did not produce compounds with antagonist properties. 16 Because of the distinct differences between the phenyl-equatorial 543-hydroxypheny1)morphans and the 4,5-epoxymorphinans in: structure, activities of optical isomers, and structure-activity relationships (SAR) of "antagonist" groups, the chemical modification of this class of compounds to improve or alter selectivity at opioid receptors was of great interest.…”

mentioning

confidence: 99%

Probes for Narcotic Receptor-Mediated Phenomena. 20. Alteration of Opioid Receptor Subtype Selectivity of the 5-(3-Hydroxyphenyl)morphans by Application of the Message-Address Concept: Preparation of .delta.-Opioid Receptor Ligands

Bertha¹,

Flippen‐Anderson²,

Rothman³

et al. 1995

J. Med. Chem.

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Derivatives of racemic and optically active 5-(3-hydroxyphenyl)-2-methylmorphan (5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1) were synthesized containing additional aromatic moieties, as an application of the message-address concept targeted at producing delta-opioid receptor selective ligands. In vitro radioreceptor binding studies in rat brain revealed that both of the parent enantiomers, (-)- and (+)-1, had a high affinity for the mu-opioid receptor (21 nM), a slight affinity for kappa 1-opioid receptors (approximately 800-900 nM), and less than 1000 nM affinity for the delta-opioid receptor (mu/delta IC50 ratio of < 0.02 for both). A derivative of (-)-1 containing an indole moiety fused at the C6-C7 position of the phenylmorphan nucleus, (-)-11, displayed a > 180-fold increase in affinity for the delta-opioid receptor with an IC50 value of 6 nM. The parent compound (-)-1 had only 26% agonist activity at 30 microM in the mouse vas deferens (delta) bioassay, whereas compound (-)-11 had an IC50 of 393 nM in this preparation, indicating the importance of the indole moiety in imparting delta-opioid agonist activity to the phenylmorphan (-)-11. A structure-activity relationship (SAR) study of N-alkyl derivatives of the racemic nor 11 indicated similarities between the interaction of various derivatives with the mu- and delta- but not the kappa 1-opioid receptor. As studies on the molecular basis of the interaction of opioid ligands with their respective receptors continue to gain momentum, the SAR data described herein for the synthetic phenylmorphans will prove useful for further studies.

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mentioning

confidence: 99%

Probes for Narcotic Receptor-Mediated Phenomena. 20. Alteration of Opioid Receptor Subtype Selectivity of the 5-(3-Hydroxyphenyl)morphans by Application of the Message-Address Concept: Preparation of .delta.-Opioid Receptor Ligands

Bertha¹,

Flippen‐Anderson²,

Rothman³

et al. 1995

J. Med. Chem.

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“…Usually (although not always), the enantiomer of an opioid-like compound has little or no affinity for opioid receptors. However, in an early study by Ong et al, 27 the (+)-enantiomer of an N -methyl-substituted phenylmorphan was found to be three times more potent than morphine in antinociceptive assays in mice; its (−)-enantiomer was comparable to morphine as an antinociceptive and it was nalorphine-like as an antagonist in morphine-dependent monkeys. This was discovered (in 1974) before opioid receptor assays were widely available, and it is difficult to compare the results from animal assays to contemporary receptor assays; nevertheless, one of the phenylmorphan enantiomers of Ong et al, 27 was found to be a potent agonist, and the other enantiomer had (weak) antagonist properties, albeit agonist properties as well in vivo.…”

Section: Resultsmentioning

confidence: 97%

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

Truong

Hassan

Lee

et al. 2017

Bioorganic & Medicinal Chemistry

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The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(−) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the μ,-opioid receptor (e.g., 1R,5R,9S-16: Ki = 0.073, 0.74, and 1.99 nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy μ-agonists (EC50 = 0.74 and 18.5 nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S, 5S,9R-16 was unusual, it had good affinity for the μ-OR (Ki = 26.5 nM) and was an efficacious μ-antagonist (Ke = 29.1 nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16 μ-agonist and the previously synthesized (1R,5R,9S)-(−)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(−)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.

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“…The morphan 37 is locked into an equatorial 3-hydroxyphenyl conformation but is an opioid agonist. 171 This was used to formulate additional pharmacophoric requirements in determining the antagonist activity of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of compounds. The additional pharmacophoric requirement can be satisfied by a substituent in the 3-axial position.…”

Section: 2) 34-dimethyl-4-(3-hydroxyphenyl)piperidine Class Of Opimentioning

confidence: 99%

“…Thus, it was not surprising to find that N-methyl-5-(3-hydroxyphenyl)morphan (37) is an agonist. 171 The opioid antagonist model developed in the previous section would predict that agonist activity would be hindered by 4 -methyl and 9 -methyl groups in the 5-(3-hydroxyphenyl)morphans ( Figure 7). Thus, the model predicted that N-methyl-4 -methyl-5-(3-hydroxyphenyl)morphan (38) and N-methyl-9 -5-(3-hydroxyphenyl)morphan (39a) would be pure opioid antagonists.…”

Section: 2) 34-dimethyl-4-(3-hydroxyphenyl)piperidine Class Of Opimentioning

confidence: 99%

2002 Medicinal Chemistry Division Award Address: Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy

Carroll

2003

J. Med. Chem.

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Phenylmorphan agonists-antagonists

Cited by 35 publications

References 1 publication

Probes for Narcotic Receptor-Mediated Phenomena. 20. Alteration of Opioid Receptor Subtype Selectivity of the 5-(3-Hydroxyphenyl)morphans by Application of the Message-Address Concept: Preparation of .delta.-Opioid Receptor Ligands

Probes for Narcotic Receptor-Mediated Phenomena. 20. Alteration of Opioid Receptor Subtype Selectivity of the 5-(3-Hydroxyphenyl)morphans by Application of the Message-Address Concept: Preparation of .delta.-Opioid Receptor Ligands

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

2002 Medicinal Chemistry Division Award Address: Monoamine Transporters and Opioid Receptors. Targets for Addiction Therapy

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