Opioid binding and in vitro profiles of a series of 4-hdroxy-3-methoxyindolomorphinans. Transformation of a delta-selective ligand into a high affinity kappa-selective ligand by introduction of a 5,14-substituted bridge.
In investigation of the effects of 14-substitution in the indolomorphinan series of delta-selective opioid ligands, 5,14-bridged indolomorphinans (4) were prepared from the equivalent dihydrothebainone acid-catalyzed rearrangement products of the dihydrothevinols. Though the new ligands generally had low affinity for opioid receptors and no delta-selectivity, 4b had high kappa-affinity and substantial selectivity which was also seen in the precursor morphinanone (3b). This indicates that the methylbenzylidene-substituted bridge in these compounds is a dominant kappa-opioid receptor binding motif.
Grundt
Peter
P
Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.
Martinez-Bermejo
Fernando
F
Lewis
John W
JW
Husbands
Stephen M
SM
D000818:Animals; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism
D001952:Bridged-Ring Compounds; D007211:Indoles; D008024:Ligands; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu