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

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-Ala 2, MePhe 4, Gly 5-ol)-enkephalin (DAMGO) and its Gly 5-NH 2 congener (DAMGA). Endomorphin-1-ol (Tyr-Pro-Trp-Phe-ol) had an IC 50 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.