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Probes for narcotic receptor mediated phenomena. 40. N-substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols.

ABSTRACT: A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2-methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxide-bridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-para-fluorophenethyl derivative had the highest mu-opioid receptor affinity of the examined compounds (K(i)=0.35 microM).

SUBMITTER: Iyer MR

PROVIDER: S-EPMC2818504 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Probes for narcotic receptor mediated phenomena. 40. N-substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols.

Iyer Malliga R MR Lee Yong Sok YS Deschamps Jeffrey R JR Rothman Richard B RB Dersch Christina M CM Jacobson Arthur E AE Rice Kenner C KC

Bioorganic & medicinal chemistry 20091118 1

A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2-methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxide-bridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-para-fluorophenethyl derivative h ...[more]

PMID: 20005115

Similar Datasets

Probes for narcotic receptor mediated phenomena 49. N-substituted rac-cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols.

Project description:Racemic N-substituted -1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols containing cis-4a-aralkyl groups were explored as probes for opioid receptors. Specifically cis-4a-phenylpropyl, -phenylbutyl, and-phenylpentyl groups coupled with widely varied substituents on the nitrogen atom were synthesized and their pharmacological profiles at opioid receptors examined. The study yielded compounds with good affinity and moderate to potent antagonist activity at the ?- and ?-opioid receptors, and agonist activity at the ?-opioid receptor. An N-allyl substituent in the C4a phenylpropyl series induced 6-fold higher affinity at ?-than ?-receptors, while an N-CPM substituent in the C4a (CH2)3Ph series led to a compound with high ?-affinity and potent ?-antagonist activity.

| S-EPMC4348089 | biostudies-literature

Probes for narcotic receptor mediated phenomena. 39. Enantiomeric N-substituted benzofuro[2,3-c]pyridin-6-ols: synthesis and topological relationship to oxide-bridged phenylmorphans.

Project description: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.

| S-EPMC2788676 | biostudies-literature

Probes for narcotic receptor mediated phenomena. 46. N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols - carbocyclic relatives of f-oxide-bridged phenylmorphans.

Project description: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 ?-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 ?-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent ?-antagonists, with activities comparable to naltrexone in the [(35)S]GTP-?-S assay.

| S-EPMC3569853 | biostudies-literature

Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation.

Project description: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 ?-opioid receptor, rather than the ?- or ?-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances ?-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.

| S-EPMC3817624 | biostudies-other

Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective ?-antagonist activity.

Project description: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 ?-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 ?-opioid receptor (K(i) = 4.6 nM). Compound 4b was a moderately potent ?-opioid antagonist (K(e) = 12 nM), as determined by [(35)S]GTP-?-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 ? or ?-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 ?-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.

| S-EPMC3340882 | biostudies-literature

Probes for narcotic receptor mediated phenomena. 41. Unusual inverse ?-agonists and potent ?-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans.

Project description:Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher ?-affinity than the compound with an N-phenylpropyl substituent (K(i) = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [(35)S]GTP-?-S functional binding assay using nondependent cells that stably express the cloned human ?-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent ?-opioid antagonists ((+)-29, K(e) = 0.17 and (-)-30, K(e) =0.3) in the [(35)S]GTP-?-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their ?-opioid receptor affinity in terms of the spatial position of N-substituents.

| S-EPMC3047451 | biostudies-literature

(4aR*,8aS*)-2,3-Diphenyl-4a,5,6,7,8,8a-hexa-hydro-quinoxaline.

Project description:In the title compound, C(20)H(20)N(2), the quinoxaline ring adopts a very distorted half-chair conformation [N=C-C=N = 22.7?(2)° for the nominally coplanar atoms] and the cyclo-hexane ring adopts a chair conformation. The quinoxaline and cyclo-hexane rings are cis-fused. The two phenyl rings form a dihedral angle of 63.88?(7)°.

| S-EPMC3394007 | biostudies-literature

(4aR,8aR)-2,3-Diphenyl-4a,5,6,7,8,8a-hexa-hydro-quinoxaline.

Project description:The title mol-ecule, C(20)H(20)N(2), is chiral; the absolute configuration follows from the known chirality of the input reagents. In addition to van der Waals forces, C-H?? ring inter-actions are also present. The angle between the planes of the phenyl rings is 65.6?(1)°. The heterocyclic ring of the quinoxaline system has a twist-boat configuration, while the cyclohexane ring has a chair configuration.

| S-EPMC2960268 | biostudies-literature

1-(4a,8-Dimethyl-1,2,3,4,4a,5,6,8a-octa-hydro-naphthalen-2-yl)-3-phenyl-prop-2-en-1-one.

Project description:The title compound, C(21)H(26)O, was semisynthesized from isocostic acid, isolated from the aerial part of Inula Viscosa- (L) Aiton [or Dittrichia Viscosa- (L) Greuter]. The cyclo-hexene ring has a half-chair conformation, whereas the cyclo-hexane ring displays a chair conformation.

| S-EPMC3100077 | biostudies-literature

rac-(4aR,8aR)-2,3-Diphenyl-4a,5,6,7,8,8a-hexa-hydro-quinoxaline.

Project description:The structure of the title racemic compound, C(20)H(20)N(2), shows close similarity to that of the enanti-omerically pure (4aR,8aR)-2,3-diphenyl-4a,5,6,7,8,8a-hexa-hydro-quinoxaline [Wang & Ye (2008 ?). Acta Cryst. E64, o359-o359]. The similarity applies to the unit-cell parameters as well as to the packing of the constituent mol-ecules. Similar packing is conditioned by a lack of directed inter-molecular inter-actions such as hydrogen bonds in either structure.

| S-EPMC2961730 | biostudies-literature

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