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 δ-Opioid Receptor Ligands

Craig M. Bertha, Judith L. Flippen-Anderson, Richard B. Rothman, Frank Porreca, Peg Davis, Heng Xu, Karen Becketts, Xian Yuan Cha, Kenner C. Rice

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Derivatives of racemic and optically active 5-(3-hydroxyphenyl)-2-methylmorphan (5-(3- hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1) were synthesized containing additional aromatic moieties, as an application of the message-address concept targeted at producing (5-opioid receptor selective ligands. In vitro radioreceptor binding studies in rat brain revealed that both of the parent enantiomers, (−)- and (+)-1, had a high affinity for the μ-opioid receptor (21 nM), a slight affinity for κ1-opioid receptors (~800–900 nM), and less than 1000 nM affinity for the δ-opioid receptor (μ/δ IC50 ratio of <0.02 for both). A derivative of (−)-l containing an indole moiety fused at the C6–C7 position of the phenylmorphan nucleus, (−)-11, displayed a > 180-fold increase in affinity for the δ-opioid receptor with an IC50 value of 6 nM. The parent compound (−)-l had only 26% agonist activity at 30 μM in the mouse vas deferens (δ) bioassay, whereas compound (−)-11 had an IC50 of 393 nM in this preparation, indicating the importance of the indole moiety in imparting ó-opioid agonist activity to the phenylmorphan (−)-11. A structure–activity relationship (SAR) study of N-alkyl derivatives of the racemic nor 11 indicated similarities between the interaction of various derivatives with the μ- and δ- but not the κ1-opioid receptor. As studies on the molecular basis of the interaction of opioid ligands with their respective receptors continue to gain momentum, the SAR data described herein for the synthetic phenylmorphans will prove useful for further studies.

Original languageEnglish (US)
Pages (from-to)1523-1537
Number of pages15
JournalJournal of Medicinal Chemistry
Volume38
Issue number9
DOIs
StatePublished - Apr 1 1995

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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