title: 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.
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.
authors.affiliation: 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.
authors.forename: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.affiliation: 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.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.affiliation: 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.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.affiliation: 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.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.affiliation: 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.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D006575:Heterocyclic Compounds, 3-Ring; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
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