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

Malliga R Iyer; Richard B Rothman; Christina M Dersch; Arthur E Jacobson; Kenner C Rice

doi:10.1016/j.ejmech.2015.01.025

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

Eur J Med Chem. 2015 Mar 6:92:531-9. doi: 10.1016/j.ejmech.2015.01.025. Epub 2015 Jan 13.

Authors

Malliga R Iyer¹, Richard B Rothman², Christina M Dersch², Arthur E Jacobson¹, Kenner C Rice³

Affiliations

¹ Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA; Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA.
² Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
³ Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA; Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA. Electronic address: kennerr@mail.nih.gov.

Abstract

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 μ- and δ-opioid receptors, and agonist activity at the κ-opioid receptor. An N-allyl substituent in the C4a phenylpropyl series induced 6-fold higher affinity at δ-than μ-receptors, while an N-CPM substituent in the C4a (CH2)3Ph series led to a compound with high δ-affinity and potent δ-antagonist activity.

Keywords: Opioid receptors; Synthesis; [(35)S]GTP-γ-S efficacy assays; cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols; μ-and δ-receptor antagonists.

Published by Elsevier Masson SAS.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Dose-Response Relationship, Drug
Heterocyclic Compounds, 3-Ring / chemical synthesis
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology*
Humans
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Receptors, Opioid, delta / antagonists & inhibitors*
Receptors, Opioid, kappa / agonists*
Receptors, Opioid, mu / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Benzofurans
Heterocyclic Compounds, 3-Ring
Piperidines
Receptors, Opioid, delta
Receptors, Opioid, kappa
Receptors, Opioid, mu

Grants and funding

Z99 DA999999/Intramural NIH HHS/United States