morphine and phenylmorphan

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

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

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 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