Receptor constants for endomorphin-1 and endomorphin-1-ol indicate differences in efficacy and receptor occupancy

Mahmoud Al-Khrasani, György Orosz, László Kocsis, Viktor Farkas, Anna Magyar, Imre Lengyel, Sándor Benyhe, Anna Borsodi, András Z. Rónai

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30 Citations (Scopus)

Abstract

The opioid properties of endomorphin derivatives containing a C-terminal alcoholic(-ol) function were compared to the parent amidated compounds in isolated organs (longitudinal muscle strip of guinea-pig ileum and mouse vas deferens). Similar data were also generated for the μ-opioid receptor selective agonist synthetic peptide (D-Ala2, MePhe4, Gly5-ol)-enkephalin (DAMGO) and its Gly5-NH2 congener (DAMGA). Endomorphin-1-ol (Tyr-Pro-Trp-Phe-ol) had an IC50 of 80.6 nM in mouse vas deferens and 61.2 nM in guinea-pig ileum; the corresponding values for endomorphin-2-ol (Tyr-Pro-Phe-Phe-ol) were 49.6 and 48.2 nM, for DAMGO 59.8 and 29.2 nM, respectively. As it was indicated by the antagonism by naltrexone, the agonist actions were exerted exclusively at μ-opioid receptors in both organs. The -ol derivatives were slightly (2.3-4.3 times) less potent than the parent amides in the bioassays: all peptides had, apparently, full agonist properties in intact preparations. With the aim of revealing potential partial agonist properties among the investigated peptides, we partially inactivated the μ-opioid receptor pool in mouse vas deferens by 5 × 10-7 M β-funaltrexamine. The calculated receptor constants indicated a "high-affinity, low intrinsic efficacy" profile (i.e. a potential partial agonist property) for endomorphin-1, an intermediate character for endomorpin-1-ol and full agonism for DAMGA and DAMGO. Apparently, a higher receptor fraction remained accessible for endomorphin-1 (42.8%) than for the -ol congener (14.0%), DAMGO (20.2%) and DAMGA (14.1%) after partial inactivation.

Original languageEnglish
Pages (from-to)61-67
Number of pages7
JournalEuropean Journal of Pharmacology
Volume421
Issue number1
DOIs
Publication statusPublished - jún. 1 2001

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ASJC Scopus subject areas

  • Pharmacology

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