A κ opioid pharmacophore becomes a spinally selective κ-δ Agonist when modified with a basic extender arm

Ye Tang, Jie Yang, Mary M. Lunzer, Michael D. Powers, Philip S. Portoghese

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We have explored the concept of a molecular extender arm attached to a κ opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact with a complementary group on a neighboring opioid receptor. The molecular arm containing a terminal amine group was lengthened incrementally from 11 up to 18 atoms. Increasing the number of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency. In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16-atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED50 ratio of ∼130. Further lengthening led to a decreased ED50 ratio. In vivo selective antagonist studies of KDA-16 revealed that κ and δ opioid receptors were responsible for the greatly enhanced i.t. potency. Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate κ-δ heteromers. These data are consistent with the reported possible presence of heteromeric κ-δ opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics.

Original languageEnglish (US)
Pages (from-to)7-10
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume2
Issue number1
DOIs
StatePublished - Jan 13 2011

Keywords

  • Opioid receptors
  • heteromers
  • molecular extender arm

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