morphinans and phenylmorphan

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation,

Topics: Analgesics, Opioid; Morphinans; Morphine; Receptors, Opioid, mu

The 5-(3-hydroxy)phenylmorphan structural class of compounds are unlike the classical morphinans, 4,5-epoxymorphinans, and 6,7-benzomorphans, in that they have an equatorially oriented aromatic ring rather than the axial orientation of that ring found in the classical opioids. This modified and simplified opioid-like structure has been shown to retain antinociceptive activity, depending on its stereochemistry and substituents, and some of them have been found to be much more potent than morphine. A simple C9-hydroxy-5-(3-hydroxy)phenylmorphan enantiomer was found to be about 500 times more potent than morphine in vivo. We have previously examined C9-alkenyl and hydroxyalkyl substituents in the

Topics: Analgesics, Opioid; Morphinans; Morphine; Naltrexone; Receptors, Opioid, mu; Structure-Activity Relationship

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).

Topics: Crystallography, X-Ray; Isomerism; Morphinans; Oxides; Receptors, Opioid, mu

The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced "one pot" diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the μ-opioid receptor, rather than the δ- or κ-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances μ-receptor affinity, bringing the Ki to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses.

Topics: Alkylation; Animals; Cells, Cultured; CHO Cells; Cricetulus; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Conformation; Morphinans; Receptors, Opioid; Stereoisomerism; Structure-Activity Relationship

A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo[3.2.1]octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple inversion of the stereochemistry at C-4. Both N-methyl (3a and 4a) and N-phenethyl (3b and 4b) derivatives were synthesized. The compounds were examined for their opioid receptor affinity and the N-phenethyl analogue 3b was found to have relatively weak affinity for the μ-opioid receptor (K(i) = 74 nM). However, the N-phenethyl analogue of the C-4 epimer, 4b, had about 15 fold higher affinity than 3b and was selective for the μ-opioid receptor (K(i) = 4.6 nM). Compound 4b was a moderately potent μ-opioid antagonist (K(e) = 12 nM), as determined by [(35)S]GTP-γ-S assays. Compounds 3b and 4b were energy minimized at the level of B3LYP/6-31G*, and then overlaid onto the 5-phenylmorphan, the (1R,5R,9S)-(-)-enantiomer of 2b (Fig. 1) with the α or β-OH group at the C-9 position. The spatial orientation of the hydroxyl moiety in 3b, 4b, 2a, and 2b is proposed to be the structural requirement for high μ-opioid receptor binding affinity and their agonist or antagonist activity. The modest change in spatial position of the hydroxyl moiety, and not the N-substituent, induced the change from potent agonist to an antagonist of moderate potency.

Topics: Animals; Azabicyclo Compounds; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Guanosine 5'-O-(3-Thiotriphosphate); Molecular Structure; Morphinans; Narcotic Antagonists; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Stereoisomerism; Structure-Activity Relationship

Oxide-bridged phenylmorphans were conceptualized as topologically distinct, structurally rigid ligands with 3-dimensional shapes that could not be appreciably modified on interaction with opioid receptors. An enantiomer of the N-phenethyl-substituted ortho-f isomer was found to have high affinity for the μ-receptor (K(i) = 7 nM) and was about four times more potent than naloxone as an antagonist. In order to examine the effect of introduction of a small amount of flexibility into these molecules, we have replaced the rigid 5-membered oxide ring with a more flexible 6-membered carbon ring. Synthesis of the new N-phenethyl-substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols resulted in a two carbon-bridged relative of the f-isomers, the dihydrofuran ring was replaced by a cyclohexene ring. The carbocyclic compounds had much higher affinity and greater selectivity for the μ-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent μ-antagonists, with activities comparable to naltrexone in the [(35)S]GTP-γ-S assay.

Topics: Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Conformation; Morphinans; Oxides; Receptors, Opioid, mu; Structure-Activity Relationship

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan(rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest μ-opioid receptor affinity (K(i)=1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([³⁵S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist.

Topics: Crystallography, X-Ray; Molecular Conformation; Morphinans; Narcotic Antagonists; Oxides; Protein Binding; Receptors, Opioid; Stereoisomerism

N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for μ- and κ-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at μ- and κ-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for μ- and κ-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate μ- and κ-opioid antagonist activity in the [(35)S]GTP-γ-S assay (K(e)=31 and 26 nM).

Topics: Animals; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Conformation; Morphinans; Narcotic Antagonists; Oxides; Stereoisomerism; Structure-Activity Relationship

Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzyl-4-aryl-1,2,3,6-tetrahydropyridine by a highly efficient and diastereoselective reaction series, "one-pot" alkylation and ene-imine cyclization followed by sodium borohydride reduction. Mild cyclization conditions gave the desired substituted 5-phenylmorphans in good yield as a single diastereomer.

Topics: Alkylation; Cyclization; Models, Molecular; Molecular Structure; Morphinans; Stereoisomerism

Enantiomers of N-substituted benzofuro[2,3-c]pyridin-6-ols have been synthesized, and the subnanomolar affinity and potent agonist activity of the known racemic N-phenethyl substituted benzofuro[2,3-c]pyridin-6-ol can now be ascribed to the 4aS,9aR enantiomer. The energy-minimized structures suggest that the active enantiomer bears a greater three-dimensional resemblance to morphine than to an ostensibly structurally similar oxide-bridged phenylmorphan. Structural features of the conformers of N-substituted benzofuro[2,3-c]pyridin-6-ols were compared to provide the rationale for their binding affinity.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Models, Molecular; Molecular Conformation; Morphinans; Nitrogen; Oxides; Pyridines; Quantum Theory; Receptors, Opioid; Stereoisomerism

The N-phenethyl analogues of (1R*,4aR*,9aS*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol and 8-ol and (1R*,4aR*,9aR*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-6-ol and 8-ol, the ortho- (43) and para-hydroxy e- (20), and f-oxide-bridged 5-phenylmorphans (53 and 26) were prepared in racemic and enantiomerically pure forms from a common precursor, the quaternary salt 12. Optical resolutions were accomplished by salt formation with suitable enantiomerically pure chiral acids or by preparative HPLC on a chiral support. The N-phenethyl (-)- para-e enantiomer (1S,4aS,9aR-(-)-20) was found to be a mu-opioid agonist with morphine-like antinociceptive activity in a mouse assay. In contrast, the N-phenethyl (-)-ortho-f enantiomer (1R,4aR,9aR-(-)-53) had good affinity for the mu-opioid receptor (K(i) = 7 nM) and was found to be a mu-antagonist both in the [(35)S]GTP-gamma-S assay and in vivo. The molecular structures of these rigid enantiomers were energy minimized with density functional theory at the level B3LYP/6-31G* level, and then overlaid on a known potent mu-agonist. This superposition study suggests that the agonist activity of the oxide-bridged 5-phenylmorphans can be attributed to formation of a seven membered ring that is hypothesized to facilitate a proton transfer from the protonated nitrogen to a proton acceptor in the mu-opioid receptor.

Topics: Animals; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Haplorhini; Mice; Models, Chemical; Molecular Structure; Morphinans; Narcotic Antagonists; Oxygen; Phenylethyl Alcohol; Quantum Theory; Stereoisomerism

In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.

Topics: Benzofurans; Crystallography, X-Ray; Isomerism; Molecular Conformation; Molecular Structure; Morphinans; Oxides; Pyridines

The opioid receptor binding affinities of N-methyl- and N-phenethyl-5-phenylmorphans with a meta-hydroxy substituent [3-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1a), and 3-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1b)] were compared with the affinities of four new ligands bearing an ortho- or para-hydroxyl substituent (2-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2a) and 2-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2b), 4-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3a), and 4-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3b)) that were synthesized from 2-bromoanisole or the known 2-methyl-5-phenyl-2-azabicyclo[3.3.1]nonane (13), respectively. The data indicated that either the electronic state of the phenolic ring is critical for the ligand's interaction with an opioid receptor, or that there must be a specific distance and angle for a hydrogen bond between the phenolic moiety and an amino acid in the binding domain that cannot be altered.

Topics: Animals; Ligands; Morphinans; Phenols; Receptors, Opioid

The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained tetracyclic trans-fused 5,6-ring system in rac-(1alpha,4aalpha,9aalpha)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((+/-)-11), although preference for cis ring fusion during the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-crystal X-ray crystallographic study of the desired para-e isomer ((+/-)-2), as well as of two intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand that would enable interaction with opioid receptors as agonists or antagonists.

Topics: Bridged-Ring Compounds; Crystallography, X-Ray; Fluorine; Molecular Probes; Molecular Structure; Morphinans; Receptors, Opioid; Stereoisomerism

The morphine-like (+)-phenylmorphan, the atypical (-)-enantiomer, and some analogues have been tested in receptor binding assays selective for opioid mu 1, mu 2, delta, kappa 1, and kappa 3 receptors. The affinities of all of the compounds except one, including the atypical (-)-phenylmorphan, were greatest for mu 1 and mu 2 receptors. The only exception was the (+)-9 alpha-methyl analogue which had slightly greater affinity for the kappa 1 receptor. The selective receptor binding assays provide evidence that opioids in which the phenyl ring is constrained to be equatorial on the piperidine ring can have considerable affinity for mu receptors. In addition, dose-response curves were determined for (+)- and (-)-phenylmorphan using the mouse tail-flick assay with the (+)-enantiomer found to be about 7 times more potent. Pretreatment with the selective opioid antagonists beta-FNA (mu 1 and mu 2), naloxonazine (mu 1), nor-BNI (kappa 1), and naltrindole (delta) suggests that the antinociceptive activity of both enantiomers is mediated through mu receptors. The pretreatment with naloxonazine, which attenuated the antinociceptive effect, shows that both (+)- and (-)-phenylmorphan are mu 1 agonists while intrathecal administration shows that both are mu 2 agonists. Conformational energy calculations on the compounds were also performed using the MM2-87 program. Consistent with previous conformational results for the phenylmorphans (J. Med. Chem. 1984, 27, 1234-1237), the most potent antinociceptive compounds preferred a particular orientation of the phenyl ring.

Topics: Analgesics; Animals; Male; Mice; Molecular Conformation; Morphinans; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship; Substrate Specificity

The conformational preferences of phenylmorphan have been determined by the MM2 (Molecular Mechanics II) program using full energy minimization. Chair-chair conformations of the cyclohexane and piperidine rings were preferred by 2.6 kcal/mol or more. With the preferred chair-chair conformation, three stable orientations of the phenyl ring were found with relative energies of 0.0, 1.0, and 1.2 kcal/mol. The barrier to rotation of the phenyl ring was computed to be 4 kcal/mol. The preferred phenyl orientation for the (+)-antipode was similar to that of morphine using a previously postulated molecular model for opiate substrates. This is consistent with the typical morphine-like pharmacological properties of this antipode. The preferred phenyl orientation of the atypical (-)-antipode appears to be most similar to the phenyl orientation that is invariably preferred by more active prodine antipodes. The preferred conformer was similar to the one observed by X-ray crystallography.

Topics: Molecular Conformation; Morphinans; Morphine; Stereoisomerism; Structure-Activity Relationship; X-Ray Diffraction