A critical structural determinant of opioid receptor interaction with phenolic 5-phenylmorphans.
The opioid receptor binding affinities of N-methyl- and N-phenethyl-5-phenylmorphans with a meta-hydroxy substituent [3-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1a), and 3-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1b)] were compared with the affinities of four new ligands bearing an ortho- or para-hydroxyl substituent (2-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2a) and 2-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2b), 4-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3a), and 4-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3b)) that were synthesized from 2-bromoanisole or the known 2-methyl-5-phenyl-2-azabicyclo[3.3.1]nonane (13), respectively. The data indicated that either the electronic state of the phenolic ring is critical for the ligand's interaction with an opioid receptor, or that there must be a specific distance and angle for a hydrogen bond between the phenolic moiety and an amino acid in the binding domain that cannot be altered.
Kim
In Jong
IJ
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0815, USA.
Dersch
Christina M
CM
Rothman
Richard B
RB
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D000818:Animals; D008024:Ligands; D009019:Morphinans / Q000737:chemistry*; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D009019:Morphinans; D010636:Phenols; D011957:Receptors, Opioid; C042531:phenylmorphan