title: Probes for narcotic receptor mediated phenomena. 47. Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols.
abstract: A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a-l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both μ- and δ-opioid receptors. A C4a-phenethyl derivative 2a, was found to have modest receptor affinity both at μ- (K(i)=60 nM) and δ-opioid receptors (K(i)=64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified to obtain compounds with different N-substituents that might provide higher affinity at both receptors. A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding studies and functional assays revealed a moderately selective δ-antagonist (2l), selective μ-δ antagonists (3d, 3g), and a μ-κ antagonist (3f).
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and The National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-9415, USA.
authors.forename: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013462:Sulfur Radioisotopes; D014316:Tritium
chemical_list: D008024:Ligands; D009292:Narcotic Antagonists; D011725:Pyridines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate)