Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies

Mariana Spetea, Petra Windisch, Yan Guo, Indre Bileviciute-Ljungar, Johannes Schütz, Muhammad Faheem Asim, Ilona P. Berzetei-Gurske, P. Riba, Kornel Kiraly, S. Fürst, M. Al-Khrasani, Helmut Schmidhammer

Research output: Article

8 Citations (Scopus)

Abstract

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

Original languageEnglish
Pages (from-to)980-988
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number4
DOIs
Publication statusPublished - febr. 24 2011

Fingerprint

Opioid Receptors
Glycine
Opioid Analgesics
Analgesics
Pharmacology
Carrageenan
Hyperalgesia
Morphine
Tail
compound 18

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies. / Spetea, Mariana; Windisch, Petra; Guo, Yan; Bileviciute-Ljungar, Indre; Schütz, Johannes; Asim, Muhammad Faheem; Berzetei-Gurske, Ilona P.; Riba, P.; Kiraly, Kornel; Fürst, S.; Al-Khrasani, M.; Schmidhammer, Helmut.

In: Journal of Medicinal Chemistry, Vol. 54, No. 4, 24.02.2011, p. 980-988.

Research output: Article

Spetea, Mariana ; Windisch, Petra ; Guo, Yan ; Bileviciute-Ljungar, Indre ; Schütz, Johannes ; Asim, Muhammad Faheem ; Berzetei-Gurske, Ilona P. ; Riba, P. ; Kiraly, Kornel ; Fürst, S. ; Al-Khrasani, M. ; Schmidhammer, Helmut. / Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 4. pp. 980-988.
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