Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series

Zsuzsanna Fürst, Beáta Búzás, Tamás Friedmann, Helmut Schmidhammer, A. Borsodi

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The newly synthesized 14-alkoxymetopon derivatives, 14-methoxymetopon, 14-methoxy-5-methylmorphinone, exhibit high affinity for the naloxone binding sites in rat brain. A substantial decrease in affinity was observed, in the presence of NaCl indicating a high degree of agonist activity. All three 14-alkoxymetopon derivatives displayed high affinity for [3H][D-Ala2,(Me)Phe4,Gly-ol5]enkephalin ([3H]DAMGO) binding sites, much less potency toward δ sites and were the least effective at κ sites. Isolated tissue studies using the guinea pig ileum preparation confirmed their high agonist potency. Following administration the new compounds produced naloxone reversible antinociceptive effects and were 130-300 times more potent than morphine in the acetic acid induced abdominal constriction model in the mouse, and the hot plate and tail flick tests in the rat. The compounds also produced dose-dependent muscle rigidity, and potentiated barbiturate-induced narcosis. The in vivo apparent pA2 values for naloxone against 14-ethoxymetopon and morphine were similar in analgesia, suggesting an interaction with the same (μ) receptor site. The dependence liability of 14-alkoxymetopon derivatives in the withdrawal jumping test was less pronounced than that of morphine in either rats or mice, similar to tolerance to the their analgesic action. It is concluded that the 14-alkoxymetopon derivatives studied are selective and potent agonists at μ opioid receptors, with reduced dependence liability.

Original languageEnglish
Pages (from-to)209-215
Number of pages7
JournalEuropean Journal of Pharmacology
Volume236
Issue number2
DOIs
Publication statusPublished - May 19 1993

Fingerprint

Opioid Receptors
Naloxone
Morphine
Binding Sites
Muscle Rigidity
Stupor
Enkephalins
Ileum
Constriction
Acetic Acid
Analgesia
Analgesics
Tail
Guinea Pigs
Brain

Keywords

  • (Binding)
  • 14-Alkoxymetopons
  • Analgesia
  • Opioid receptors
  • Physical dependence

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series. / Fürst, Zsuzsanna; Búzás, Beáta; Friedmann, Tamás; Schmidhammer, Helmut; Borsodi, A.

In: European Journal of Pharmacology, Vol. 236, No. 2, 19.05.1993, p. 209-215.

Research output: Contribution to journalArticle

Fürst, Zsuzsanna ; Búzás, Beáta ; Friedmann, Tamás ; Schmidhammer, Helmut ; Borsodi, A. / Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series. In: European Journal of Pharmacology. 1993 ; Vol. 236, No. 2. pp. 209-215.
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