PROBES FOR NARCOTIC RECEPTOR-MEDIATED PHENOMENA .20. ALTERATION OF OPIOID RECEPTOR SUBTYPE SELECTIVITY OF THE 5-(3-HYDROXYPHENYL)MORPHANS BY APPLICATION OF THE MESSAGE-ADDRESS CONCEPT - PREPARATION OF DELTA-OPIOID RECEPTOR LIGANDS

Derivatives of racemic and optically active 5-(3-hydroxyphenyl)-2-meth ylmorphan hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1) were s ynthesized containing additional aromatic moieties, as an application of the message-address concept targeted at producing delta-opioid rece ptor selective ligands. In vitro radioreceptor binding studies in rat brain revealed that both of the parent enantiomers, (-)- and (+)-1, ha d a high affinity for the mu-opioid receptor (21 nM), a slight affinit y for kappa(1)-opioid receptors (similar to 800-900 nM), and less than 1000 nM affinity for the delta-opioid receptor (mu/delta IC50 ratio o f (0.02 for both). A derivative of(-)-1 containing an indole moiety fu sed at the C6-C7 position of the phenylmorphan nucleus, (-)-11, displa yed a > 180-fold increase in affinity for the delta-opioid receptor wi th an IC50 value of 6 nM. The parent compound (-)-1 had only 26% agoni st activity at 30 mu M in the mouse vas deferens (delta) bioassay, whe reas compound (-)-11 had an IC50 Of 393 nM in this preparation, indica ting the importance of the indole moiety in imparting delta-opioid ago nist activity to the phenylmorphan (-)-11. A structure-activity relati onship (SAR) study of N-alkyl derivatives of the racemic nor 11 indica ted similarities between the interaction of various derivatives with t he mu- and delta- but not the kappa(1)-opioid receptor. As studies on the molecular basis of the interaction of opioid ligands with their re spective receptors continue to gain momentum, the SAR data described h erein for the synthetic phenylmorphans will prove useful for further s tudies.